Non-steroidal ligands for the glucocorticoid receptor, compositions and uses thereof

ABSTRACT

The invention provides non-steroidal ligands for the glucocorticoid receptor, methods for making non-steroidal ligands of the glucocorticoid receptor, compositions of non-steroidal ligands of the glucocorticoid receptor and methods of using non-steroidal ligands and compositions of non-steroidal ligands of the glucocorticoid receptor for treating or preventing diseases (e.g., obesity, diabetes, depression, neurodegeneration or an inflammatory disease) associated with glucocorticoid binding to the glucocorticoid receptor.

CLAIM OF PRIORITY

This application is a continuation application of U.S. patentapplication Ser. No. 12/365,106, filed on Feb. 3, 2009, now U.S. Pat.No. 7,947,726, which application is a continuation application of U.S.patent application Ser. No. 10/972,250, filed on Oct. 22, 2004, now U.S.Pat. No. 7,485,660, which is a divisional application of U.S. patentapplication Ser. No. 10/350,260, filed on Jan. 22, 2003, now U.S. Pat.No. 6,831,093, which claims benefit of priority to U.S. provisionalpatent application Ser. Nos. 60/351,484, filed on Jan. 22, 2002 and60/373,757, filed on Apr. 17, 2002, all of which are incorporated hereinby reference in their entirety.

ACKNOWLEDGMENT

This invention was made with government support under DK57574 awarded bythe National Institutes of Health. The government has certain rights inthe invention.

TECHNICAL FIELD

The present invention relates generally to non-steroidal ligands of theglucocorticoid receptor, methods for making non-steroidal ligandscompositions of non-steroidal ligands, and methods for usingnon-steroidal ligands, and methods for using compositions ofnon-steroidal ligands. More specifically, the present invention relatesto derivatives of Wieland-Miescher ketone, methods for makingderivatives of Wieland-Miescher ketone, compositions of derivatives ofWieland-Miescher ketone, methods for using derivatives ofWieland-Miescher ketone, and methods for using compositions ofderivatives of Wieland-Miescher ketone.

BACKGROUND

The glucocorticoid receptor is a member of the steroid/thyroid nuclearhormone receptor superfamily, which includes, but is not limited to,mineralcorticoid, androgen, progesterone and estrogen receptors. Theglucocorticoid receptor is activated in vivo by binding of naturalagonists such as cortisol and corticosterone. The glucocorticoidreceptor may also be activated by binding of synthetic agonists such asdexamethasone, prednisone and prednisilone. Many synthetic antagonistsof glucocorticoid receptors (e.g., RU-486) are also known.

Since the presence or absence of ligand binding to the glucocorticoidreceptor may have profound physiological consequences (e.g., lead toCushing's syndrome or Addison's disease), drugs that target theglucocorticoid receptor are clinically relevant. Consequently, selectiveglucocorticoid receptor ligands that either activate (i.e., agonists) orinactivate (i.e., antagonists) glucocorticoid mediated response arecompounds of pharmaceutical interest.

The glucocorticoid receptor, when activated by ligand, mediatesbiological processes (e.g., metabolism, electrolyte balance, organ andtissue systems, etc.) by binding to specific regulatory DNA sequences(i.e., response elements) in the promoter of cortisol-regulated genes.The glucocorticoid receptor may thus activate or repress transcriptionof cortisol-regulated genes. At least three different response elementsexist for glucocorticoid receptor regulation: (1) the glucocorticoidresponse element (GRE); (2) an AP-1/GRE; and (3) a NFκB/GRE. Agonistbinding to the glucocorticoid receptor leads to transcriptionalactivation of the GRE and transcriptional repression of AP-1/GRE andNFκB/GR.

Currently available drugs that bind to the glucocorticoid receptor aretypically cortisol analogues, which produce undesired side effects thatare caused by: (1) unselective binding to other steroid receptors; and(2) failure to disassociate the different response elements when bindingto the glucocorticoid receptor. Thus, there exists a need for compoundsthat selectively bind to the glucocorticoid receptor and selectivelydisassociate the different response elements of the glucocorticoidreceptor.

SUMMARY

The present invention addresses these and other needs by providingnon-steroidal ligands for the glucocorticoid receptor, methods formaking non-steroidal ligands of the glucocorticoid receptor,compositions of non-steroidal ligands of the glucocorticoid receptor andmethods of using non-steroidal ligands and compositions of non-steroidalligands of the glucocorticoid receptor for treating or preventingdiseases (e.g., obesity, diabetes, depression, neurodegeneration or aninflammatory disease) associated with glucocorticoid binding to theglucocorticoid receptor. In principle, the current invention allows forthe preparation of either agonist or antagonist compounds and either orboth of these pharmacological modes of action may be useful for certaintherapeutic treatments.

The compounds of the instant invention include a carbocyclic ringsystem, which may be unsaturated and may be annelated with aheterocyclic ring. In particular, the carbocyclic ring systems may be anindan (i.e., a six membered carbocyclic ring fused with a five memberedcarbocyclic ring), a dehydro-decalin (i.e., a six membered carbocyclicring fused with a six membered carbocyclic ring) or a dehydro [4.5.0]bicyclo undecane (i.e., a six membered carbocyclic ring fused with aseven membered carbocyclic ring) ring system. When the carbocylic ringsystem comprises a carbocyclic ring system annelated with a heterocyclicring, the heterocyclic ring is typically attached to the six memberedring fragment—say of an indan or a dehydro-decalin—and has at least oneoxygen, nitrogen or sulfur atom.

In a first aspect, the present invention provides compounds of formula(I):

or a pharmaceutically available salt, solvate or hydrate thereofwherein:

A, B and C are independently carbon, nitrogen, oxygen or sulfur providedthat at least one of A, B and C is nitrogen, oxygen or sulfur and thatno more than one of A, B and C are oxygen or sulfur;

W is carbon, oxygen, nitrogen, or sulfur and, when W is other thancarbon and nitrogen, one or more of R₈, R₉ and R₁₀ is absent so that anormal valence on W is maintained;

R₁ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,acylamino, substituted acylamino, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl,substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl,aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substitutedcarbamoyl, carboxy, cyano, halo, heteroalkyl or substituted heteroalkyl,heteroarylalkyl or substituted heteroarylalkyl;

R₂, R₃, R₅, R₆, R₆′, and R₇ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, acylamino, substitutedacylamino, alkoxy, substituted alkoxy, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl,substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl,alkylthio, substituted alkylthio, alkoxycarbonyl, substitutedalkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl,substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy,cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl,substituted heteroarylalkyl or hydroxy;

R₂′, R₃′, R₅′, R₇′ and R₈ are absent or are independently hydrogen,alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substitutedacylamino, alkoxy, substituted alkoxy, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl,substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl,alkylthio, substituted alkylthio, alkoxycarbonyl, substitutedalkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl,substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy,cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl,substituted heteroarylalkyl or hydroxy;

R₄ is absent or is hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, acylamino, substituted acylamino, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl,substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl,aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substitutedcarbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl,heteroarylalkyl or substituted heteroarylalkyl;

R₉ is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, alkylamino, substituted alkylamino, dialkylamino, substituteddialkylamino, carboxy, cyano, halo, oxo, thio, hydroxy or is absent;

R₁₀ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, aryloxycarbonyl, substitutedaryloxycarbonyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, or is absent;

R₁₀ and R₂ may bond directly to one another to form a ring, and anadditional ring such as a benzene ring, which may itself be substitutedwith an alkyl, alkoxy, halo, alkyl, substituted alkyl, acyl, substitutedacyl, cycloalkyl, or substituted cycloalkyl, may fuse to the bondbetween R₁₀ and R₂; and

R₁₁ and R₁₂ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, acylamino, substituted acylamino, alkoxy, substitutedalkoxy, amino, alkylamino, substituted alkylamino, dialkylamino,substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl,alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substitutedaryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo,oxo, thio, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy.

The bonds in formula (I) that are shown with single and dashed lines areintended to represent alternative forms of the structure. That is, oneor more, but preferably one, such bonds may be a double bond providedthat normal valences of the atoms in the rings are satisfied.

In a second aspect, the present invention provides compositions ofcompounds of the invention. The compositions generally comprise one ormore compounds of the invention, pharmaceutically acceptable salts,hydrates or solvates thereof and a pharmaceutically acceptable diluent,carrier, excipient and adjuvant. The choice of diluent, carrier,excipient and adjuvant will depend upon, among other factors, thedesired mode of administration.

In a third aspect, the present invention provides methods for treatingor preventing obesity, diabetes, depression, neurodegeneration or aninflammatory disease. The methods generally involve administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of a compound and/or composition of the invention.

In a fourth aspect, the current invention provides compositions fortreating or preventing obesity, diabetes, depression, neurodegenerationor an inflammatory disease in a patient in need of such treatment orprevention.

In a fifth aspect the current invention provides methods for selectivelymodulating the activation, repression, agonism and antagonism effects ofthe glucocorticoid receptor in a patient. The methods generally involveadministering to patient in need of such treatment a therapeuticallyeffective amount of a compound or composition of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows synthesis Scheme 1, for a preferred synthetic route to aketone intermediate used for synthesis of the compounds of structuralformula (I).

FIG. 2 shows synthesis Scheme 2 for derivatizing an intermediate shownin Scheme 1.

FIG. 3 shows synthesis Scheme 3 for derivatizing a compound shown inScheme 2.

FIG. 4 shows synthesis Scheme 4 for derivatizing a compound shown inScheme 2.

FIG. 5 shows synthesis Scheme 5 for derivatizing a number of ketonemoieties.

FIG. 6 shows synthesis Scheme 6 for synthesizing compounds of thepresent invention.

FIG. 7 shows synthesis Scheme 7 for synthesizing compounds of thepresent invention.

DETAILED DESCRIPTION Definitions

“Compounds of the invention” refers to compounds encompassed bystructural Formula (I) disclosed herein and includes any specificcompounds within that formula whose structure is disclosed herein. Thecompounds of the invention may be identified either by chemicalstructure and/or chemical name. When the chemical structure and chemicalname conflict, the chemical structure is determinative of the identityof the compound. The compounds of the invention may contain one or morechiral centers and/or double bonds and therefore, may exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers),enantiomers or diastereomers. Accordingly, the chemical structuresdepicted herein encompass all possible enantiomers and stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure or diastereomericallypure), and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to an artisan of ordinary skill The compounds ofthe invention may also exist in several tautomeric forms including theenol form, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds.

The compounds of the invention also include isotopically labeledcompounds where one or more atoms have an atomic mass different from themost abundant atomic mass normally found in nature for given atom.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O,¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.

Furthermore it should be understood that, when partial structures of thecompounds of the invention or precursors thereto are illustrated,brackets of dashes indicate the point of attachment of the partialstructure to the rest of the molecule.

“Alkyl” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include radicals having anydegree or level of saturation, i.e., groups having exclusivelycarbon-carbon single bonds, groups having one or more carbon-carbondouble bonds, groups having one or more carbon-carbon triple bonds andgroups having mixtures of single, double and triple carbon-carbon bonds.Where a specific level of saturation is intended, the expressions“alkanyl”, “alkenyl”, and “alkynyl” are used. Preferably, an alkyl groupcomprises from 1 to 20 carbon atoms, more preferably from 1 to 10 carbonatoms or still more preferably from 1 to 6 carbon atoms.

“Alkanyl” refers to a saturated branched, straight-chain or cyclic alkylradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. Typical alkanyl groups include, but are notlimited to, methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such asbutan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon double bond, derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkene. The various groups attached to the double bond(s) may be ineither the cis or trans (or E, or Z) conformation about the doublebond(s). Typical alkenyl groups include, but are not limited to,ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; penta-2,4-diene, andthe like.

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon triple bond, derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such asbut-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” refers to a radical —C(═O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acylamino” refers to a radical —NR′C(═O)R, where R′ and R are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein.Representative examples include, but are not limited to, formylamino,acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,benzoylamino, benzylcarbonylamino and the like.

“Alkylamino” means a radical —NHR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylamino, ethylamino, 1-methylethylamino,cyclohexylamino and the like.

“Alkoxy” refers to a radical —OR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy andthe like.

“Alkoxycarbonyl” refers to a radical —C(═O)-alkoxy where alkoxy is asdefined herein.

“Alkylsulfonyl” refers to a radical —S(═O)₂R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

“Alkylsulfinyl” refers to a radical —S(═O)R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkylgroup as defined herein that may be optionally substituted as definedherein. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, and the like.

“Amino” refers to the radical —NH₂.

“Aryl” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from fused ring systems that comprise one or morearomatic rings, or conjugated ring systems, such as aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, heptaphene, hexacene, hexaphene,as-indacene, s-indacene, indene, naphthalene (hexalene), octacene,octaphene, octalene, ovalene, pentacene, pentalene, pentaphene,perylene, phenalene, phenanthrene, picene, pleiadene, pyrene,pyranthrene, rubicene, tetraphenylene, triphenylene, trinaphthalene andthe like. Additionally, aryl groups include fused ring systemscontaining at least one aromatic ring and at least one partiallysaturated ring, such as fluorene, indane, biphenylene and the like.Preferably, an aryl group comprises from 6 to 20 carbon atoms, morepreferably between 6 to 12 carbon atoms.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³hybridized carbon atom, is replaced with an aryl group. Typicalarylalkyl groups include, but are not limited to, benzyl,2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylalkenyl and/orarylalkynyl is used. Preferably, an arylalkyl group is (C₆-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkylgroup is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀), more preferably, anarylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₈) and the aryl moiety is(C₆-C₁₂).

“Arylalkyloxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein.

“Aryloxycarbonyl” refers to a radical —C(═O)—O-aryl where aryl is asdefined herein.

“Carbamoyl” refers to the radical —C(═O)N(R)2 where each R group isindependently hydrogen, alkyl, cycloalkyl or aryl as defined herein,which may be optionally substituted as defined herein.

“Carboxy” means the radical —C(═O)OH.

“Cyano” means the radical —CN.

“Cycloalkyl” refers to a saturated or unsaturated cyclic alkyl radical.Where a specific level of saturation is intended, the nomenclature“cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groupsinclude, but are not limited to, groups derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like. Preferably, thecycloalkyl group is C₃-C₁₀ cycloalkyl, more preferably C₃-C₇ cycloalkyl.

“Cycloheteroalkyl” refers to a saturated or unsaturated cyclic alkylradical in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Typical cycloheteroalkyl groups include, but are not limitedto, groups derived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Cycloheteroalkyloxycarbonyl” refers to a radical —C(═O)—OR where R iscycloheteroalkyl as defined herein.

“Dialkylamino” means a radical —NRR' where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein. Representativeexamples include, but are not limited to dimethylamino,methyl-ethylamino, di-(1-methylethyl)amino, cyclohexyl-methyl amino,cyclohexyl-ethyl amino, cyclohexyl-propyl amino, and the like.

“Halo” means fluoro, chloro, bromo, or iodo.

“Heteroalkyloxy” means an —O-heteroalkyl radical where heteroalkyl is asdefined herein.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” refer toalkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which oneor more of the carbon atoms (and any associated hydrogen atoms) are eachindependently replaced with the same or different heteroatomic groups.Typical heteroatomic groups include, but are not limited to, —O—, —S—,—O—O—, —S—S—, —O—S—, —NR′—, ═N—N═, —N═N—, —N═N—NR′—, —PH—, —P(O)₂—,—O—P(O)₂—, —S(O)—, —S(O)₂—, —SnH₂— and the like, wherein R′ is hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl orsubstituted aryl.

“Heteroaryl” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,

-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup has from 5-20 non-hydrogen atoms, with 5-10 non-hydrogen atomsbeing particularly preferred. Preferred heteroaryl groups are thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole and pyrazine.

“Heteroaryloxycarbonyl” refers to a radical —C(═O)—OR where R isheteroaryl as defined herein.

“Heteroarylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³hybridized carbon atom, is replaced with a heteroaryl group. Wherespecific alkyl moieties are intended, the nomenclatureheteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is used.Preferably, the heteroarylalkyl radical has 6-30 non-hydrogen atoms,e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl isC₁₋₁₀ and the heteroaryl moiety is a 5-20 membered heteroaryl, morepreferably, a 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenylor alkynyl moiety of the heteroarylalkyl is 1-8 membered and theheteroaryl moiety is a 5-12 membered heteroaryl.

“Hydroxy” means the radical —OH.

“Oxo” means the divalent radical —O.

“Prodrug” refers to a pharmacologically inactive derivative of a drugmolecule that requires a transformation within the body to release theactive drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.Ideally, the promoiety is rapidly cleared from the body upon cleavagefrom the prodrug.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in Green et al., “ProtectiveGroups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991) and Harrison etal., “Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wileyand Sons, 1971-1996). Representative amino protecting groups include,but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl“(”CBZ″), tert-butoxycarbonyl (“Boc”), trimethylsilyl(“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyprotecting groups include, but are not limited to, those where thehydroxy group is either acylated or alkylated such as benzyl, and tritylethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers and allyl ethers.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R¹⁴, —O⁻, ═O,—OR¹⁴, —SR¹⁴, —S⁻, ═S, —NR¹⁴R¹⁵, ═NR¹⁴, —CX₃, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R¹⁴, —OS(O₂)O⁻,—OS(O⁻)₂R¹⁴, —P(O)(O⁻)₂, —P(O)(OR¹⁴)(O⁻), —OP(O)(OR¹⁴)(OR¹⁵), —C(O)R¹⁴,—C(S)R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁵, —C(O)O⁻, —C(S)OR¹⁴, —NR¹⁶C(O)NR¹⁴R¹⁵,—NR¹⁶C(S)NR¹⁴R¹⁵, —NR¹⁷C(NR¹⁶)NR¹⁴R¹⁵ and —C(NR¹⁶)NR¹⁴R¹⁵, where each Xis independently a halogen; each R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, —NR¹⁸R¹⁹, —C(O)R¹⁸ or —S(O)₂R¹⁸ oroptionally R¹⁸ and R¹⁹ together with the atom to which they are bothattached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;and R¹⁸ and R¹⁹ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted alkyl, arylalkyl, substituted alkyl, cycloalkyl,substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

“Thio” means the radical —SH.

“Valence” refers to the number of bonds that an atom forms. In organicchemistry this ordinarily means that no unpaired electrons areassociated with an atom in its normal valence when bonded in achemically stable molecule. Thus, for example, the normal valence ofcarbon is 4, hydrogen is 1, nitrogen is 3, oxygen is 2, sulfur is 2, andthe halogens each have a normal valence of 1.

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, modifications, and equivalents as maybe included within the spirit and scope of the invention as defined bythe appended claims.

The Compounds of the Invention

The compounds of the invention include compounds of formula (I):

or a pharmaceutically available salt, solvate of hydrate thereofwherein:

A, B and C are independently carbon, nitrogen, oxygen or sulfur providedthat at least one of A, B and C is nitrogen, oxygen or sulfur and thatno more than one of A, B and C are oxygen or sulfur;

W is carbon, oxygen, nitrogen, or sulfur and when W is other than carbonand nitrogen, one or more of R₈, R₉ and R₁₀ is absent so that a normalvalence on W is maintained;

R₁ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,acylamino, substituted acylamino, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl,substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl,aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substitutedcarbamoyl, carboxy, cyano, halo, heteroalkyl or substituted heteroalkyl,heteroarylalkyl or substituted heteroarylalkyl;

R₂, R₃, R₅, R₆, R₆′, and R₇ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, acylamino, substitutedacylamino, alkoxy, substituted alkoxy, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl,substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl,alkylthio, substituted alkylthio, alkoxycarbonyl, substitutedalkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl,substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy,cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl,substituted heteroarylalkyl or hydroxy;

R₂′, R₃′, R₅′, R₇′ and R₈ are absent or are independently hydrogen,alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substitutedacylamino, alkoxy, substituted alkoxy, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl,substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl,alkylthio, substituted alkylthio, alkoxycarbonyl, substitutedalkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl,substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy,cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl,substituted heteroarylalkyl or hydroxy;

R₄ is absent or is hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, acylamino, substituted acylamino, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl,substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl,aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substitutedcarbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl,heteroarylalkyl or substituted heteroarylalkyl;

R₉ is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, alkylamino, substituted alkylamino, dialkylamino, substituteddialkylamino, carboxy, cyano, halo, oxo, thio, hydroxy or is absent;

R₁₀ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, aryloxycarbonyl, substitutedaryloxycarbonyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, or is absent;

R₁₀ and R₂ may bond directly to one another to form a ring, and anadditional ring such as a benzene ring, which may itself be substitutedwith an alkyl, alkoxy, halo, alkyl, substituted alkyl, acyl, substitutedacyl, cycloalkyl, or substituted cycloalkyl, may fuse to the bondbetween R₁₀ and R₂; and

R₁₁ and R₁₂ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, acylamino, substituted acylamino, alkoxy, substitutedalkoxy, amino, alkylamino, substituted alkylamino, dialkylamino,substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl,alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substitutedaryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo,oxo, thio, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy.

The bonds in formula (I) that are shown with single and dashed lines areintended to represent alternative forms of the structure. That is, oneor more, but preferably one, such bonds may be a double bond providedthat normal valences of the atoms in the rings are satisfied. To theextent it is necessary, when maintaining the valences of ring carbonatoms that are bonded to one another by a double bond, aring-substituent attached to one or more such ring carbon atoms may beabsent.

The present invention also includes compounds of structural formula(II):

or a pharmaceutically available salt, solvate or hydrate thereof whereinR₁, R₂, R₄, R₅, R₅′, R₆, R₆′, R₇, R₇′, R₈, R₉, R₁₀, R₁₁, R₁₂, A, B andC, and W, are as previously defined for formula (I), and R₂′ is definedin the same manner as R₅′ and R₇′ were previously defined for formula(I), and the bonds with single and dashed lines indicate alternativeisomeric forms as discussed hereinabove.

The present invention also includes compounds of structural formula(III):

or a pharmaceutically available salt, solvate or hydrate thereof,wherein R₁, R₂, ‘R₂’, R₃, R₄, R₅, R₅′, R₆, R₆′, R₇, R₇′, R₈, R₉, R₁₀,R₁₁, R₁₂, A, B and C, and W are as previously defined in formula (I) andR₃′, R₁₃ and R₁₃′ are defined in the same manner as R₂, R₂′, R₃, R₅, R₆,R₇ and R₈ were previously defined in formula (I), and the bonds withsingle and dashed lines indicate alternative isomeric forms, asdiscussed hereinabove, and wherein R₁₀ and R₁₃ (instead of R₂) may bonddirectly to one another to form a ring, and an additional ring may fuseto the bond between R₁₀ and R₁₃.

In one embodiment of compounds of structural formulae (I), (II) and(III), A, B and C are carbon or nitrogen. Preferably, A is carbon and Band C are nitrogen.

In another embodiment of compounds of structural formulae (I), (II) and(III), A, B and C are carbon, nitrogen or sulfur. Preferably, A issulfur, B is carbon and C is nitrogen.

In still another embodiment of compounds of structural formulae (I),(II) and (III), A, B and C are carbon, nitrogen or oxygen. Preferably, Ais carbon, B is oxygen and C is nitrogen or A is carbon, B is nitrogenand C is oxygen.

In a preferred embodiment of compounds of structural formulae (I), (II)and (III), W is carbon.

In another embodiment of compounds of structural formulae (I), (II) and(III), W is oxygen and bonds with a double bond to the ring carbon atomto which it is attached, and R₈, R₉ and R₁₀ are absent.

In one preferred embodiment of compounds of structural formulae (I),(II) and (III), R₁ and R₄ are independently hydrogen, alkyl, substitutedalkyl, acyl, substituted acyl, alkoxycarbonyl, substitutedalkoxycarbonyl, carboxy, cyano, carbamoyl, substituted carbamoyl,heteroalkyl or substituted heteroarylalkyl. Preferably, R₁ and R₄ areindependently hydrogen, alkyl or substituted alkyl. More preferably, R₁and R₄ are independently hydrogen or methyl.

In one embodiment of compounds of structural formula (I), R₂, R₂′, R₃,R₅, R₆, R₆′, R₇ and R₈ are independently hydrogen, alkyl, substitutedalkyl, acyl, substituted acyl, alkoxy, substituted alkoxy, amino,alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, substitutedcarbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl orhydroxy. Preferably, R₂, R₂′ R₃, R₅, R₆, R₆′, R₇ and R₈ areindependently hydrogen, alkanyl or substituted alkanyl. More preferably,R₂, R₂′ R₃, R₅, R₆, R₆′, R₇ and R₈ are hydrogen or methyl.

In an embodiment of compounds of structural formula (II), R₂, R₅, R₆,R₆′, R₇ and R₈ are independently hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, alkoxy, substituted alkoxy, amino,alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, substitutedcarbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl orhydroxy. Preferably, R₂, R₅, R₆, R₆′, R₇ and R₈ are independentlyhydrogen, alkanyl or substituted alkanyl. More preferably, R₂, R₂′, R₅,R₆, R₆′, R₇ and R₈ are hydrogen or methyl.

In an embodiment of compounds of structural formula (III), R₂, R₂′, R₃,R₃′, R₅, R₆, R₆′, R₇, R₈, R₁₃ and R₁₃′ are independently hydrogen,alkyl, substituted alkyl, acyl, substituted acyl, alkoxy, substitutedalkoxy, amino, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl,substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substitutedheteroalkyl or hydroxy. Preferably, R₂, R₂′, R₃, R₅, R₆, R₆′, R₇, R₈,R₁₃ and R₁₃′ are independently hydrogen, alkanyl or substituted alkanyl.More preferably, R₂, R₂′, R₃, R₅, R₆, R₆′, R₇, R₈, R₁₃ and R₁₃′ arehydrogen or methyl.

In an embodiment of compounds of structural formulae (I), (II) and(III), R₄ and R₅′ are absent. In another embodiment of compounds ofstructural formulae (I), (II) and (III), R₄ and R₇′ are absent. Inanother embodiment of compounds of structural formulae (I) and (III),R₃′ and R₇′ are absent. In another embodiment of compounds of structuralformulae (I) and (III), R₃′ and R₂′ are absent.

In an embodiment of compounds of structural formulae (I) and (III), R₃′,R₅′ and R₇′ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, alkoxy, substituted alkoxy, amino, alkoxycarbonyl,substituted alkoxycarbonyl, carbamoyl, substituted carbamoyl, carboxy,cyano, halo, heteroalkyl, substituted heteroalkyl or hydroxy.Preferably, R₃′, R₅′ and R₇′ are independently hydrogen, alkanyl orsubstituted alkanyl. More preferably, R₃′, R₅′ and R₇′ are hydrogen ormethyl.

In an embodiment of compounds of structural formula (II), R₂′, R₅′ andR₇′ are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, alkoxy, substituted alkoxy, amino, alkoxycarbonyl,substituted alkoxycarbonyl, carbamoyl, substituted carbamoyl, carboxy,cyano, halo, heteroalkyl, substituted heteroalkyl or hydroxy.Preferably, R₂′, R₅′ and R₇′ are independently hydrogen, alkanyl orsubstituted alkanyl. More preferably, R₂′, R₅′ and R₇′ are hydrogen ormethyl.

In another embodiment of compounds of structural formulae (I), (II) and(III), R₉ is hydrogen, alkoxy, substituted alkoxy, halo, oxo, thio orhydroxy. Preferably, R₉ is alkoxy, oxo, hydroxy or is absent.

In still another embodiment of compounds of structural formulae (I),(II) and (III), R₁₀ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, or is absent. Preferably,R₁₀ is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

In still another embodiment of compounds of structural formulae (I),(II) and (III), R₁₁ and R₁₂ are independently hydrogen, alkyl, alkoxy,amino, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, carboxy, cyano, halo,oxo, thio, heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl or hydroxy. Preferably, R₁₁and R₁₂ are independently hydrogen, aryl, substituted aryl, arylalkyl,substituted arylalkyl, oxo, heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy.More preferably, R₁₁ and R₁₂ are independently hydrogen, aryl orsubstituted aryl.

In one preferred embodiment of compounds of structural formula (I), R₁,R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇, R₇′ and R₈ are hydrogen, alkyl orarylalkyl and R₄ and R₅′ are absent. In another preferred embodiment, R₁is methyl, R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇, R₇′ and R₈ are hydrogenand R₄ and R₅′ are absent.

The following embodiments are more specific embodiments of the precedingtwo preferred embodiments. In one embodiment, R₉ is alkoxy, oxo orhydroxy. In another embodiment, R₁₀ is aryl, substituted aryl,heteroaryl or substituted heteroaryl. In still another embodiment, A iscarbon, B and C are nitrogen, R₁₁ is hydrogen and R₁₂ is aryl,substituted aryl, heteroaryl or substituted heteroaryl. In still anotherembodiment, A is sulfur, B is carbon and C is nitrogen. In still anotherembodiment, A is carbon, B is oxygen and C is nitrogen. In still anotherembodiment, A is carbon, B is nitrogen and C is oxygen.

In one preferred embodiment of compounds of structural formula (II), R₁,R₂, R₂′, R₅, R₆, R₆′, R₇, R₇′ and R₈ are hydrogen, alkyl or arylalkyland R₄ and R₅′ are absent. In another preferred embodiment, R₁ ismethyl, R₂, R₂′, R₅, R₆, R₆′, R₇, R₇′ and R₈ are hydrogen and R₄ and R₅′are absent.

The following embodiments are more specific embodiments of the precedingtwo preferred embodiments. In one embodiment, R₉ is alkoxy, oxo orhydroxy. In another embodiment, R₁₀ is aryl, substituted aryl,heteroaryl or substituted heteroaryl. In still another embodiment, A iscarbon, B and C are nitrogen, R₁₁ is hydrogen and R₁₂ is aryl,substituted aryl, heteroaryl or substituted heteroaryl. In still anotherembodiment, A is sulfur, B is carbon and C is nitrogen. In still anotherembodiment, A is carbon, B is oxygen and C is nitrogen. In still anotherembodiment, A is carbon, B is nitrogen and C is oxygen.

In one preferred embodiment of compounds of structural formula (III),R₁, R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇, R₇′, R₈, R₁₃ and R₁₃′ arehydrogen, alkyl or arylalkyl and R₄ and R₅′ are absent. In anotherpreferred embodiment, R₁ is methyl, R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇,R₇′, R₈, R₁₃ and R₁₃′ are hydrogen and R₄ and R₅′ are absent.

The following embodiments are more specific embodiments of the precedingtwo preferred embodiments. In one embodiment, R₉ is alkoxy, oxo orhydroxy. In another embodiment, R₁₀ is aryl, substituted aryl,heteroaryl or substituted heteroaryl. In still another embodiment, A iscarbon, B and C are nitrogen, R₁₁ is hydrogen and R₁₂ is aryl,substituted aryl, heteroaryl or substituted heteroaryl. In still anotherembodiment, A is sulfur, B is carbon and C is nitrogen. In still anotherembodiment, A is carbon, B is oxygen and C is nitrogen. In still anotherembodiment, A is carbon, B is nitrogen and C is oxygen.

In a preferred embodiment of compounds of structural formula (I), R₁ ismethyl, R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇, R₇′ and R₈ are hydrogen, R₄and R₅′ are absent, R₉ is alkoxy, oxo or hydroxy, R₁₀ is aryl,substituted aryl, heteroaryl or substituted heteroaryl, A is carbon, Band C are nitrogen, R₁₁ is hydrogen and R₁₂ is aryl, substituted aryl,heteroaryl or substituted heteroaryl. Preferably, R₉ is hydroxy and R₁₀is

In a preferred embodiment of compounds of structural formula (II), R₁ ismethyl, R₂, R₂′, R₅, R₆, R₆′, R₇, R₇′ and R₈ are hydrogen, R₄ and R₅′are absent, R₉ is alkoxy, oxo or hydroxy, R₁₀ is aryl, substituted aryl,heteroaryl or substituted heteroaryl, A is carbon, B and C are nitrogen,R₁₁ is hydrogen and R₁₂ is aryl, substituted aryl, heteroaryl orsubstituted heteroaryl.

In a preferred embodiment of compounds of structural formula (III), R₁is methyl, R₂, R₂′, R₅, R₆, R₆′, R₇, R₇′, R₈, R₁₃ and R₁₃′ are hydrogen,R₄ and R₅′ are absent, R₉ is alkoxy, oxo or hydroxy, R₁₀ is aryl,substituted aryl, heteroaryl or substituted heteroaryl, A is carbon, Band C are nitrogen, R₁₁ is hydrogen and R₁₂ is aryl, substituted aryl,heteroaryl or substituted heteroaryl.

In one embodiment, compounds of structural formulae (I), (II) and (III)do not include any furanyl derivatives (i.e., when one of A, B or C isoxygen, the remaining members of A, B or C are not carbon). In a morespecific embodiment, the compounds of structural formulae (I), (II) and(III) do not include compounds where C is oxygen and A and B are carbonor where A is oxygen and B and C are carbon.

In one embodiment of the compounds of structural formulae (I), R₁₀ andR₂ bond directly to one another to form a 5-membered ring, W isnitrogen, R₉ is hydrogen, R₈ and R₂′ are both absent, and a benzene ringis fused to the bond between R₁₀ and R₂. In a more specific embodiment,the benzene ring is substituted with a halogen, or an alkoxy group.

In another preferred embodiment, the compounds of structural formulae(I), (II) and (III) of do not include any thienyl derivatives (i.e.,when one of A, B or C is sulfur, the remaining members of A, B or C arenot carbon). In a more specific embodiment, the compounds of structuralformulae (I), (II) and (III) do not include compounds where C is sulfurand A and B are carbon. Preferably, in this embodiment, R₁₁ and R₁₂ arenot hydrogen and methyl, respectively.

Synthesis of the Compounds of the Invention

The compounds of the invention may be obtained via the synthetic methodsillustrated in Schemes 1-7, as shown in FIGS. 1-7, respectively.Starting materials useful for preparing compounds of the invention andintermediates thereof are commercially available or can be prepared bywell-known synthetic methods. Other methods for synthesis of thecompounds described herein are either described in the art or will bereadily apparent to the skilled artisan in view of general referenceswell-known in the art (see e.g., Green et al., “Protective Groups inOrganic Chemistry”, (Wiley, 2^(nd) ed. 1991); Harrison et al.,“Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley andSons, 1971-1996); “Beilstein Handbook of Organic Chemistry”, BeilsteinInstitute of Organic Chemistry, Frankfurt, Germany; Feiser et al.,“Reagents for Organic Synthesis”, Volumes 1-17, Wiley Interscience;Trost et al., “Comprehensive Organic Synthesis”, Pergamon Press, 1991;“Theilheimer's Synthetic Methods of Organic Chemistry”, Volumes 1-45,Karger, 1991; March, “Advanced Organic Chemistry”, Wiley Interscience,1991; Larock “Comprehensive Organic Transformations”, VCH Publishers,1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis”, JohnWiley & Sons, 1995) and may be used to synthesize the compounds of theinvention. Further, specific references for synthesizing indans,decalins and guanines are easily accessible to the ordinarily skilledartisan. Accordingly, the methods presented in the Schemes herein areillustrative rather than comprehensive.

Compounds depicted in Schemes 1-7 of FIGS. 1-7 are compounds ofstructural formula (I), or precursors thereof. Those of ordinary skillin the art will appreciate that the synthetic steps illustrated inSchemes 1-7 are also applicable to the preparation of compounds ofstructural formulae (II) and (III).

A preferred synthetic route to the compounds of structural formula (I)(and, by analogy, to compounds of structural formulae (I) or (II))proceeds through ketone 107 and/or its derivatives, which may be made bythe route depicted in Scheme 1, as depicted in FIG. 1. Six membereddione 101 is either commercially available or may be synthesized fromreadily available starting materials (the same is true for thefive-membered and seven membered analogues of dione 101). Treatment ofdione 101 with base and alkylating agent (R₁) provides alkylated dione103, which may be annelated (e.g., using a methyl vinyl ketoneequivalent and base) to yield 3-keto decalin 105. Other methods ofannelating a six-membered ring are well known to the skilled artisan,(see e.g., Jung, Tetrahedron, 32(1), 3-31, (1976)). The unsaturatedketone 105 may be selectively protected with ethanedithiol and acid toyield the unsaturated thioketal 107.

An exemplary method for converting a derivative of 107, thioketal 108(108 is an embodiment of 107 wherein R₂ and R₂′ are hydrogen) to ketal113 is illustrated in Scheme 2, as depicted in FIG. 2. Conversion of 107to enal 109 may be accomplished by forming an intermediate enol ether(e.g., using a base, such as Ph₃PCH₂OCH₃) followed by concurrentdehydrogenation and hydrolysis (e.g., Pd(OAc)₂), (see Takayama et al.,J. Org. Chem., 1992, 57, 2173). Conjugate addition (e.g., using(R₂)₂CuLi), (Coates et al., J. Org. Chem., 39, 275, (1974); Posner etal., Tet. Lett., 3215, (1977)) followed by enolate trapping with R₈Xprovides aldehyde 111, which may be converted to ketal 113 by a seriesof conventional reactions (e.g., formation of a ketal and removal of thethioketal).

Alternatively, ketone 108 may be functionalized by well-known methodssuch as aldol condensation to provide β hydroxy alcohol 123, asillustrated in Scheme 3, depicted in FIG. 3. Ketone 108 may also bealkylated using conventional methods known in the art to provide alkylderivative 125. It should be noted that when R₁, R₃, R₃′, R₅, R₆, R₇ andR₇′ are hydrogen, the compounds where R is n-butyl, benzyl andisobutenyl have been synthesized. Further, other transformations ofketone 108 will be obvious to one of ordinary skill in the art and arewithin the purview of the present invention (e.g., dehydrogenation tothe enone followed by conjugate addition and enolate trapping with anelectrophile, γ-alkylation of the enone, dialkylation of the ketone,etc.).

Ketal-enone 113 may be converted to a number of useful intermediates asillustrated in Scheme 4, as shown in FIG. 4. For example, conjugateaddition may be used to provide an R₄ substituent (e.g., (R₄)₂CuLi orR′—≡, hydroziroconocene-Cl, MeLi, CuCN, LiCl), (Coates et al., J. Org.Chem., 39, 275, (1974); Posner et al., Tet. Lett., 3215, (1977);Lipshutz et al., J. Am. Chem. Soc., 112(20), 7440, (1990)) as incompound 117. Alternatively, 113 may be converted to the γ unsaturatedalcohol 119 by treatment, for example, with oxygen, triethylamine andtriethylamine oxide (Shimizu et al., Chem. Pharm. Bull., 37(7), 1963,(1989)). The double bond of enone 113 may be hydrogenated (e.g., H₂,noble metal catalyst or CuI, LiCl, followed by tri-n-butyl tin hydride)to provide the saturated ketone 221 (Lipshutz et al., Synlett., 64,(1989)). Other transformations of enone 113 will be readily apparent tothe artisan of ordinary skill

Compounds such as 113 or 121 with a free 3-keto group may be convertedto heterocyclic compounds by the methods illustrated in Scheme 5, asshown in FIG. 5 (Hashem et al., J. Med. Chem., 19, 229, (1976); Kumar etal., J. Med. Chem., 36, 3278, (1993)). Ketone 133 may be converted toenol ether 135 (e.g., using methyl formate, sodium methoxide, THF) whichmay be transformed to pyrazole 137 (using e.g., R—NH—NH₂, acetic acid ormethanol). Ketone 133 may also be converted to β-keto ester 139 (usinge.g., diethylcarbonate, sodium methoxide, methyl iodide) which then canbe reacted with a hydrazine derivative (i.e., R—NH—NH₂) to providepyrazolone 141. Bromination of ketone 133 (e.g., bromine, chloroform)yields α-bromoketone 143, which upon reaction with a thioamide (i.e.,RCS(NH₂)) provides thiazole 145. Intermediate enol ether 135 uponreaction with hydroxylamine in the presence of acetic acid and sodiumacetate is converted to oxazole 147. Isomeric oxazole 149 is producedwhen enol ether 135 is reacted with hydroxylamine under basicconditions.

Scheme 6, depicted in FIG. 6, illustrates one possible synthetic routewhich may be used to prepare compounds of the invention.Wieland-Miescher ketone 151 may be treated with 2-methyl-2-ethyl-1,3dioxolane ethylene glycol and p-toluenesulfonic acid to provide ketal153, which may be formylated (using, e.g., sodium methoxide, methylformate) to give enol 155. Enol 155 may be reacted withp-fluorophenylhydrazine in the presence of sodium acetate provide thep-fluorophenyl pyrazole 157 which then may be deprotected (using, e.g.,HCl, methanol, THF) to provide ketone 159. Ketone 159 may be convertedto aldehyde 161 by Wittig reaction (using, e.g., potassium hexamethyldisilazide, (methoxymethyl) triphenylphosphonium chloride) andhydrolysis of the intermediate enol ether (e.g., HCl). Nucleophilicaddition of organolithium reagents to the aldehyde functionality maythen provide alcohol 163.

Preferably, R is

Illustrated in Scheme 7, depicted in FIG. 7, is a synthetic pathwaywhich may be used to prepare some non-pyrazole compounds.Wieland-Miescher ketone 151 may be converted to thioketal 165 (e.g.,ethanedithiol, p-toluenesulfonic acid, acetic acid) which can providealdehyde 167 through Wittig reaction (e.g., potassium hexamethyldisilazide, (methoxymethyl) triphenylphosphonium chloride) andhydrolysis of the intermediate enol ether (e.g., HCl).

Addition of organolithium reagents to aldehyde 167 may be used toprovide alcohol 169, which may be deprotected (e.g., HgClO₄,methanol/chloroform) to provide enone 171.

Preferably, R is

Those of ordinary skill in the art will recognize that enone 171 may beconverted to compounds such as 163 illustrated in Scheme 6 throughapplications of the methods shown in Scheme 5.

Therapeutic Uses of the Compounds of the Invention

The compounds and/or compositions of the present invention may be usedto treat diseases associated with either an excess or a deficiency ofglucocorticoids in an organism (see e.g., Dow et al., InternationalPublication No. WO 00/66522; Coghlan et al., International PublicationNo. WO 99/41257; Coghlan et al., International Publication No. WO99/41256; Coughlan et al., International Publication No. WO 00/06137;Jones et al., International Publication No. WO 96/19458).

In accordance with the present invention, a compound and/or compositionof the invention is administered to a patient, preferably a human,suffering from diseases mediated by the glucocorticoid receptor, whichinclude but are not limited to, obesity, diabetes, depression,neurodegeneration or an inflammatory disease. Further, in certainembodiments, the compounds and/or compositions of the invention areadministered to a patient, preferably a human, as a preventative measureagainst various diseases or disorders (see e.g., InternationalPublication Nos. WO 00/66522, WO 99/41251, WO 00/06137, WO 96/19456).Thus, the compounds and/or compositions of the invention may beadministered as a preventative measure to a patient having apredisposition which includes, but is not limited to, obesity, diabetes,depression, neurodegeneration or an inflammatory disease. Accordingly,the compounds and/or compositions of the invention may be used for theprevention of one disease or disorder and concurrently treating another(e.g., preventing depression and treating diabetes).

Procedures for treating diseases, which include but are not limited to,obesity, diabetes, depression, neurodegeneration or an inflammatorydisease with prior art compounds have been described in the art (seereferences above). Thus, those of ordinary skill in the art may readilyassay and use the compounds and/or compositions of structural Formulae(I), (II) and (III) to treat diseases, which include but are not limitedto, obesity, diabetes, depression, neurodegeneration or an inflammatorydisease.

Therapeutic/Prophylactic Administration

The compounds and/or compositions of the invention may be advantageouslyused in human medicine. As previously described in the precedingsection, compounds and compositions of the invention are useful for thetreatment or prevention of diseases, which include, but are not limitedto, obesity, diabetes, depression, neurodegeneration or an inflammatorydisease

When used to treat or prevent disease or disorders, compounds and/orcompositions of the invention may be administered or applied singly, orin combination with other agents. The compounds and/or compositions ofthe invention may also be administered or applied singly, or incombination with other pharmaceutically active agents, including othercompounds and/or of the invention.

The current invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acomposition and/or compound of the invention. The patient may be ananimal, is more preferably a mammal and most preferably a human.

The present compounds and/or compositions of the invention, whichcomprise one or more compounds of the invention, are preferablyadministered orally. The compounds and/or compositions of the inventionmay also be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa,etc.). Administration can be systemic or local. Various delivery systemsare known, (e.g., encapsulation in liposomes, microparticles,microcapsules, capsules, etc.) that can be used to administer a compoundand/or composition of the invention. Methods of administration include,but are not limited to, intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, oral, sublingual,intranasal, intracerebral, intravaginal, transdermal, rectally, byinhalation, or topically, particularly to the ears, nose, eyes, or skin.The preferred mode of administration is left to the discretion of thepractitioner, and will depend in-part upon the site of the medicalcondition. In most instances, administration will result in the releaseof the compounds and/or compositions of the invention into thebloodstream.

In specific embodiments, it may be desirable to administer one or morecompounds and/or composition of the invention locally to the area inneed of treatment. This may be achieved, for example, and not by way oflimitation, by local infusion during surgery, topical application, e.g.,in conjunction with a wound dressing after surgery, by injection, bymeans of a catheter, by means of a suppository, or by means of animplant, said implant being of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes, or fibers.In one embodiment, administration can be by direct injection at the site(or former site) of the disease.

In certain embodiments, it may be desirable to introduce one or morecompounds and/or compositions of the invention into the central nervoussystem by any suitable route, including intraventricular, intrathecaland epidural injection. Intraventricular injection may be facilitated byan intraventricular catheter, for example, attached to a reservoir, suchas an Ommaya reservoir.

A compound and/or composition of the invention may also be administereddirectly to the lung by inhalation. For administration by inhalation, acompound and/or composition of the invention may be convenientlydelivered to the lung by a number of different devices. For example, aMetered Dose Inhaler (“MDI”), which utilizes canisters that contain asuitable low boiling propellant, (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or anyother suitable gas) may be used to deliver compounds of the inventiondirectly to the lung.

Alternatively, a Dry Powder Inhaler (“DPI”) device may be used toadminister a compound and/or composition of the invention to the lung.DPI devices typically use a mechanism such as a burst of gas to create acloud of dry powder inside a container, which may then be inhaled by thepatient. DPI devices are also well known in the art. A popular variationis the multiple dose DPI (“MDDPI”) system, which allows for the deliveryof more than one therapeutic dose. For example, capsules and cartridgesof gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch for these systems.

Another type of device that may be used to deliver a compound and/orcomposition of the invention to the lung is a liquid spray device.Liquid spray systems use extremely small nozzle holes to aerosolizeliquid drug formulations that may then be directly inhaled into thelung.

In one embodiment, a nebulizer is used to deliver a compound and/orcomposition of the invention to the lung. Nebulizers create aerosolsfrom liquid drug formulations by using, for example, ultrasonic energyto form fine particles that may be readily inhaled (see e.g., Verschoyleet al., British J. Cancer, 80, Suppl. 2, 96, (1999), which isincorporated herein by reference). Examples of nebulizers includedevices supplied by Sheffield/Systemic Pulmonary Delivery Ltd. (see,Armer et al., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat.No. 5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974), Aventis,and Batelle Pulmonary Therapeutics.

In another embodiment, an electrohydrodynamic (“EHD”) aerosol device isused to deliver a compound and/or composition of the invention to thelung. EHD aerosol devices use electrical energy to aerosolize liquiddrug solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No.4,765,539). EHD aerosol devices may deliver drugs to the lung moreefficiently than other pulmonary delivery technologies.

In another embodiment, the compounds of the invention can be deliveredin a vesicle, in particular a liposome (see Langer, Science,249:1527-1533, (1990); Treat et al., in “Liposomes in the Therapy ofInfectious Disease and Cancer”, Lopez-Berestein and Fidler (eds.), Liss,New York, pp. 353-365, (1989); see generally “Liposomes in the Therapyof Infectious Disease and Cancer”, Lopez-Berestein and Fidler (eds.),Liss, New York, (1989)).

In yet another embodiment, the compounds of the invention can bedelivered via sustained release systems, preferably oral sustainedrelease systems. In one embodiment, a pump may be used (see Langer,supra; Sefton, CRC Crit. Ref. Biomed. Eng., 14:201, (1987); Saudek etal., New Engl. J. Med., 321:574, (1989)).

In another embodiment, polymeric materials can be used (see “MedicalApplications of Controlled Release”, Langer and Wise (eds.), CRC Press,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability”, Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem., 23:61,(1983); see also Levy et al., Science, 228: 190, (1985); During et al.,Ann. Neurol., 25:351, (1989); Howard et al, J. Neurosurg., 71:105,(1989)). In a preferred embodiment, polymeric materials are used fororal sustained release delivery. In another embodiment, enteric-coatedpreparations can be used for oral sustained release administration. Instill another embodiment, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,26:695-708, (2000)).

In yet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds and/or composition of theinvention, thus requiring only a fraction of the systemic dose (see,e.g., Goodson, in “Medical Applications of Controlled Release”, supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, Science, 249:1527-1533, (1990), may also be used.

Compositions of the Invention

The present compositions contain a therapeutically effective amount ofone or more compounds of the invention, preferably in purified form,together with a suitable amount of a pharmaceutically acceptablevehicle, so as to provide the form for proper administration to apatient. When administered to a patient, the compounds of the inventionand pharmaceutically acceptable vehicles are preferably sterile. Wateris a preferred vehicle when the compound of the invention isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents or pHbuffering agents. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used.

Pharmaceutical compositions comprising a compound of the invention maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes. Pharmaceutical compositions may beformulated in conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients or auxiliaries, whichfacilitate processing of compounds of the invention into preparationsthat may be used pharmaceutically. Proper formulation is dependent uponthe route of administration chosen.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., Grosswald et al., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical vehicles have been described in theart (see Remington's Pharmaceutical Sciences, Philadelphia College ofPharmacy and Science, 17th Edition, 1985).

For topical administration, compounds of the invention may be formulatedas solutions, gels, ointments, creams, suspensions, etc., as iswell-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration. Systemic formulationsmay be made in combination with a further active agent that improvesmucociliary clearance of airway mucus or reduces mucous viscosity. Theseactive agents include, but are not limited to, sodium channel blockers,antibiotics, N-acetyl cysteine, homocysteine and phospholipids.

In a preferred embodiment, the compounds of the invention are formulatedin accordance with routine procedures as a composition adapted forintravenous administration to human beings. Typically, compounds of theinvention for intravenous administration are prepared as solutions insterile isotonic aqueous buffer. For injection, a compound of theinvention may be formulated in aqueous solutions, preferably inphysiologically compatible buffers such as Hanks' solution, Ringer'ssolution, or physiological saline buffer. The solution may containformulatory agents such as suspending, stabilizing and/or dispersingagents. When necessary, the compositions may also include a solubilizingagent. Compositions for intravenous administration may optionallyinclude a local anesthetic such as lignocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as alyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. When the compound of the invention is administered byinfusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. When thecompound of the invention is administered by injection, an ampoule ofsterile water for injection or saline solution can be provided so thatthe ingredients may be mixed prior to administration.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known to one of ordinary skill in the art.

Compositions for oral delivery may be in the form of, for example,tablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs. Orally administeredcompositions may optionally contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry coloring agentsand preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, when in tablet or pill form, the compositions maybe coated to delay disintegration and absorption in the gastrointestinaltract, thereby providing a sustained action over an extended period oftime. Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds ofthe invention. In these latter platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, and the like. Suchvehicles are preferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5.0 mM to about 50.0 mM, etc). Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

For buccal administration, the compositions may take the form oftablets, lozenges, etc., formulated in conventional manner.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as an alcohol, glycol, polyglycol or a fatty acid. Othermethods of formulating liquid drug solutions or suspension suitable foruse in aerosol devices are known to those of skill in the art (see e.g.,Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).

A compound of the invention may also be formulated in rectal or vaginalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, a compound of theinvention may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, a compound of the invention may be formulated with suitablepolymeric or hydrophobic materials (for example, as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

When a compound of the invention is acidic, it may be included in any ofthe above-described formulations as the free acid, a pharmaceuticallyacceptable salt, a solvate or hydrate. Pharmaceutically acceptable saltssubstantially retain the activity of the free acid, may be prepared byreaction with bases and tend to be more soluble in aqueous and otherprotic solvents than the corresponding free acid form.

Methods of Use and Doses

A compound of the invention and/or compositions thereof, will generallybe used in an amount effective to achieve the intended purpose. For useto treat or prevent diseases or disorders such as obesity, diabetes,depression, neurodegeneration or an inflammatory disease, the compoundsof the invention and/or compositions thereof, are administered orapplied in a therapeutically effective amount.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition and can be determinedby standard clinical techniques known in the art as previouslydescribed. In addition, in vitro or in vivo assays may optionally beemployed to help identify optimal dosage ranges. The amount of acompound of the invention administered will, of course, be dependent on,among other factors, the subject being treated, the weight of thesubject, the severity of the affliction, the manner of administrationand the judgment of the prescribing physician.

For example, the dosage may be delivered in a pharmaceutical compositionby a single administration, by multiple applications or controlledrelease. In a preferred embodiment, the compounds and/or compositions ofthe invention are delivered by oral sustained release administration.Preferably, in this embodiment, the compounds and/or compositions of theinvention are administered twice per day (more preferably, once perday). Dosing may be repeated intermittently, may be provided alone or incombination with other drugs and may continue as long as required foreffective treatment of the disease state or disorder.

Suitable dosage ranges for oral administration are dependent on thepotency of the compound of the invention, but are generally about 0.001mg to about 200 mg of a compound of the invention per kilogram bodyweight. Dosage ranges may be readily determined by methods known to theskilled artisan.

Suitable dosage ranges for intravenous (i.v.) administration are about0.01 mg to about 100 mg per kilogram body weight. Suitable dosage rangesfor intranasal administration are generally about 0.01 mg/kg body weightto about 1 mg/kg body weight. Suppositories generally contain about 0.01milligram to about 50 milligrams of a compound of the invention perkilogram body weight and comprise active ingredient in the range ofabout 0.5% to about 10% by weight. Recommended dosages for intradermal,intramuscular, intraperitoneal, subcutaneous, epidural, sublingual orintracerebral administration are in the range of about 0.001 mg to about200 mg per kilogram of body weight. Effective doses may be extrapolatedfrom dose-response curves derived from in vitro or animal model testsystems. Such animal models and systems are well known in the art.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetheradministration of a specific compound of the invention or a combinationof compounds of the invention is preferred for reducing convulsion. Thecompounds of the invention may also be demonstrated to be effective andsafe using animal model systems.

Preferably, a therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating disease and disorders. The dosage of a compound of theinventions described herein will preferably be within a range ofcirculating concentrations that include an effective dose with little orno toxicity.

Combination Therapy

In certain embodiments, the compounds of the invention can be used incombination therapy with at least one other therapeutic agent. Thecompound of the invention and the therapeutic agent can act additivelyor, more preferably, synergistically. In a preferred embodiment, acompound of the invention is administered concurrently with theadministration of another therapeutic agent. In another preferredembodiment, a composition comprising a compound of the invention isadministered concurrently with the administration of another therapeuticagent, which can be part of the same composition as the compound of theinvention or a different composition. In another embodiment, acomposition comprising a compound of the invention is administered priorto or subsequent to, administration of another therapeutic agent. Othertherapeutic agents which may be used with the compounds and/orcompositions of the invention, include but are not limited to, drugsused to treat neurodegenerative diseases such as Alzheimer's orParkinson's disease, anxiety, depression, psychosis, diabetes, obesity,etc. (see, e.g., Dow et al., International Publication No. WO 00/66522).

EXAMPLES

The invention is further defined by reference to the following examples,which describe in detail preparation of compounds and compositions ofthe invention and assays for using compounds and compositions of theinvention. It will be apparent to those of ordinary skill in the artthat many modifications, both to materials and methods, may be practicedwithout departing from the scope of the invention.

All synthetic reactions were performed under an argon atmosphere unlessotherwise noted. THF was purified by distillation from sodiumbenzophenone ketyl before use. All other anhydrous reagents werepurchased from Aldrich Chemical Co. Proton and carbon-13 nuclearmagnetic resonance spectra (¹H NMR, ¹³C NMR) were obtained on a VarianINOVA-400 (400 MHz) instrument; ¹H NMR chemical shifts are reported as δvalues in parts per million (ppm) downfield from internaltetramethylsilane; ¹³C NMR chemical shifts are reported as δ values withreference to the solvent peak (CDCl₃ or DMSO). High resolution massspectrometry (HR-MS) was performed by the National Bioorganic andBiomedical Mass Spectrometry Resource at the University of California,San Francisco.

Example 1 Preparation of5,5-(Ethylenedioxy)-4a-methyl-2,3,4,4a,5,6,7,8-octahydronaphtalen-2-one(201)

A mixture of Wieland-Miescher ketone (5.086 g, 28.44 mmol),2-methyl-2-ethyl-1,3-dioxolane (19.38 mL, 155.0 mmol), ethylene glycol(0.358 mL, 6.43 mmol) and p-toluenesulfonic acid monohydrate (0.4 g,2.13 mmol) was stirred at room temperature for 30 hours. The reactionwas quenched with dropwise addition of triethylamine, diluted with 20 mLof benzene, washed with water, dried over MgSO₄, and concentrated undervacuum. The product was triturated from hexanes to yield monoacetal 201(5.92 g, 94%). ¹H NMR (CDCl₃) δ 1.36 (s, 3H), 1.6-2.0 (m, 5H), 2.2-2.5(m, 5H), 3.9-4.1 (m, 4H), 5.80 (d, J=Hz, 1H); ¹³C NMR (CDCl₃) 198.91,167.55, 125.38, 125.37, 112.12, 65.16, 64.84, 44.81, 33.70, 31.22,29.81, 26.62, 21.51, 20.27.

Example 25,5-(Ethylenedioxy)-3-Hydroxymethylene-4a-methyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one(203)

A solution of 201 (20 g, 0.090 mmol) in THF (200 mL) was cooled to −5°C. in an ice/methanol bath. NaOMe (19.45 g, 0.360 mol) was added and themixture stirred for 30 minutes. After slow addition of a cooled solutionof methyl formate (55.5 mL, 0.900 mol) in 60 mL THF, the mixture wasstirred at room temperature for 24 hours. The mixture was poured intoice-water-HCl (˜50 mL conc. HCl in 500 mL H₂O), stirred for 5 minutesand then transferred to a separatory funnel. The aqueous layer wasextracted with ether (3×100 mL) and the pooled organic extracts werewashed with brine, dried (MgSO₄), and concentrated. The yellow residuewas flash chromatographed (0-50% EtOAc-hexanes) to yield 203 (5.88 g,26%) as a yellow oil. ¹H NMR (CDCl₃) δ 1.22 (s, 3H), 1.6-1.9 (m, 4H),2.02 (d, J=14 Hz, 1H), 2.2-2.5 (2H), 2.91 (d, J=14 Hz, 1H), 3.9-4.1 (m,4H), 5.86 (d, J=2.0 Hz, 1H), 7.37 (s, 1H); ¹³C NMR (CDCl₃) 188.72,166.86, 165.35, 165.12, 124.59, 124.25, 111.92, 106.39, 65.33, 65.17,65.04, 64.89, 46.00, 29.87, 21.33, 20.74, 20.59.

Example 31-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,6,7,8-hexahydro-benzo[f]indazol-5-one(205)

In a 250 mL round bottom flask fitted with a Dean-Stark trap andcondensor, a mixture of 203 (5.88 g, 23.5 mmol), 4-fluorophenylhydrazinehydrochloride (3.93 g, 24.2 mmol), sodium acetate (1.99 g, 24.2 mmol),and 2 mL glacial acetic acid in 150 mL benzene was heated to reflux for1 hour. During this time ˜1.2 mL of H₂O was collected. Solvents werethen evaporated and the dark residue was dissolved in ether, filtered,and concentrated to afford 8.4 g of a dark brown oil.

A mixture of this oil, 1 N HCl (25 mL), glacial acetic acid (50 mL) andTHF (75 mL) was stirred at room temperature for 48 hours. The reactionwas quenched with a saturated NaHCO₃ solution. The aqueous layer wasextracted with ether (4×50 mL), washed twice with saturated NaHCO₃,brine, and then dried (MgSO₄), and concentrated. The residue wastriturated with boiling hexanes and the combined triturates wererecrystallized from EtOH to afford 3.5 g of 205 as an orange powder.Flash chromatography (0-50% EtOAc/hexanes) of the remaining residueafforded an overall yield of 5.67 g (81% over two steps). ¹H NMR (CDCl₃)δ 1.25 (s, 3H), 1.60-1.75 (m, 1H), 2.00-2.15 (m, 1H), 2.5-2.73 (m, 4H),2.9 (d, J=3 Hz, 2H), 6.29 (d, J=2 Hz, 1H), 7.17 (t, J=8.4 Hz, 2H),7.43-7.50 (m, 3H); ¹³C NMR (CDCl₃) 212.57, 162.71, 160.25, 145.79,138.45, 135.97, 135.75, 135.71, 125.29, 125.21, 116.17, 115.94, 114.11,110.80, 50.68, 38.55, 31.56, 28.20, 23.30, 22.71; HR-MS calculated forC₁₈H₁₇FN₂O: 296.1325, found: 296.1320.

Compound 205 gave an 1050 of 436 nM in a GR binding assay.

Example 41-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazole-5-carbaldehyde(207)

To a cold (−30° C.) solution of (methoxymethyl)triphenylphosphoniumchloride (13.85 g, 40.4 mmol) in THF (40 mL), was added KHMDS (0.5M intoluene, 70.8 mL, 35.4 mmol). The resulting red solution was stirred at0° C. for 15 minutes before being treated with a solution of 205 (3 g,10.1 mmol) in THF (40 mL). The mixture was stirred at room temperaturefor 24 hours. A solution of methanol in THF (1:1, 40 mL) and 4 N HCl (30mL) was added to the mixture at 0° C. The resulting solution was allowedto stir at room temperature for 26 hours and was them poured into water(30 mL) and extracted with ether (4×50 mL). The combined organic layerswere washed with brine, dried (MgSO₄), and concentrated. Purification ofthe residue by flash chromatography on silica gel (0-50% ethylacetate-hexanes) gave 2.2 g (70%) of 207 as a yellow solid. A smallportion was further purified via bisulfite addition forcharacterization. ¹H NMR (CDCl₃) δ 1.12 (s, 3H), 1.35-1.49 (m, 1H),1.67-1.8 (m, 1H), 1.87-2.0 (m, 2H), 2.28-2.48 (m, 3H), 2.9 (d, J=16.0Hz, 1H), 3.1 (d, J=16.0 Hz, 1H), 6.18 (s, 1H), 7.16 (t, J=8.5 Hz, 2H),7.42-7.48 (m, 3H), 9.90 (d, J=2.0 Hz, 1H); ¹³C NMR (CDCl₃) 203.99,162.64, 160.18, 147.26, 137.77, 136.35, 135.65, 135.62, 125.36, 125.32,125.24, 116.09, 115.87, 113.36, 109.93, 60.78, 39.90, 34.55, 32.10,24.52, 22.62, 18.96.

Example 5 Preparation of (3-Bromo-phenoxy)-triisopropyl-silane (209)

A mixture of 3-bromophenol (1.00 g, 5.78 mmol), and imidazole (984 mg,14.45 mmol) in 6 mL of DMF was cooled to 0° C. and triisopropylsilylchloride (922 μL, 6.94 mmol) was added and the solution was stirred for24 hours. The reaction mixture was quenched with 10 mL H₂O and 5 mLsaturated aqueous NaHCO₃. The aqueous layer was extracted with ether(3×10 mL), the pooled organic extracts were washed with brine, dried(MgSO₄), and concentrated. The resulting oil was flash chromatographedon silica gel with hexanes to yield 209 (1.50 g, 79%). ¹H NMR (CDCl₃) δ1.09 (d, J=7.2 Hz, 18H), 1.17-1.30 (m, 3H), 6.75-6.81 (m, 1H), 7.00-7.10(m, 3H); ¹³C NMR (CDCl₃) 156.89, 130.26, 124.14, 123.29, 122.5, 118.47.

Example 6 (4-Bromo-3,5-dimethyl-phenoxy)-triisopropyl-silane (211)

Following the procedure of Example 5 but substituting 4-bromo-3,5dimethyl phenol for 3-bromophenol provided 211 in 93% yield. ¹H NMR(CDCl₃) δ 1.22 (d, J=6.0 Hz, 18H), 1.37 (m, 3H), 2.46 (s, 6H), 6.75 (s,2H); ¹³C NMR (CDCl₃) 154.54, 138.81, 119.65, 23.85, 17.92, 12.71.

Example 7 (4-Bromo-phenoxy)-triisopropyl-silane (213)

Following the procedure of Example 5 but substituting 4-bromophenol for3-bromophenol provided 213 in 94% yield. ¹H NMR (CDCl₃) δ 1.09 (d, J=6.8Hz), 1.23 (quint, J=7.6 Hz, 3H), 6.74 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0Hz, 2H); ¹³C NMR (CDCl₃) 155.17, 132.19, 121.56, 113.24, 17.83, 15.59.

Example 8 (4-Iodo-2-methyl-phenoxy)-triisopropyl-silane (215)

Following the procedure of Example 5 but substituting4-iodo-2methylphenol for 3-bromophenol provided 215 in 57% yield. ¹H NMR(CDCl₃) δ 1.09 (d, J=8.0 Hz, 18H), 1.26 (sext, J=8.0 Hz, 3H), 2.18 (s,3H), 6.53 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.40 (s, 1H); ¹³CNMR (CDCl₃) 154.23, 139.35, 135.36, 131.38, 119.93, 82.88, 17.97, 17.58,16.67, 12.93.

Example 9 4-Bromo-2,6-dimethoxy-phenol (217)

To a 500 mL flask fitted with a condenser, 2,6-dimethoxyphenol (10 g,64.86 mmol) and 80 mL of anhydrous CHCl₃ was added. The solution wascooled to −40° C. and NaH (60% dispersion in mineral oil, 26 mg, 0.65mmol) was added. Another 20 mL of anhydrous CHCl₃ was added followed byrapid addition of N-bromo-succinimide (12.77 g, 71.35 mmol). Thereaction mixture was stirred for 1 hour at −35° C., heated to roomtemperature over the next 30 minutes and heated to reflux for another 30minutes. The solvent was evaporated under vacuum overnight. The tansolid was stirred with 100 mL ether, the mixture was filtered, and theresidue was washed with ether. The solvent was evaporated under vacuumto yield a tan solid, which was then dissolved in boiling hexanes. Thesolution was decanted from the brown oil and filtered through apre-heated celite pad into a heated flask. The light yellow solution wasallowed to cool at room temperature for 3 hours. White wooly needleswere filtered off and dried to yield 217 (3.22 g, 22%). ¹H NMR (CDCl₃) δ6.72 (s, 2H), 5.44 (s, 1H), 3.88 (s, 6H); ¹³C NMR (CDCl₃) 147.47,133.93, 110.88, 108.38, 56.33.

Example 10 5-Bromo-1,2,3-trimethoxy-benzene (219)

A mixture of 5-bromo-1,2,3 trihydroxybenzene (1.3 g, 5.63 mmol) and 1MNaOH (14 mL) was cooled to 10° C. and dimethyl sulfate (800 μL, 16.89mmol) was added. This mixture was heated at reflux for 3 hours andanother portion of dimethyl sulfate (800 μL) was added. The mixture washeated at reflux for another 3 hours. The mixture was cooled overnight,and a gray solid was filtered off, which was then dissolved in ˜50 mLether, washed with 5% NaOH-H₂O, water (2×), brine, then dried (MgSO₄),and concentrated to yield 219 (1.39 g, 76%). ¹H NMR (CDCl₃) δ 6.72 (s,2H), 3.85 (s, 6H), 3.82 (s, 3H); ¹³C NMR (CDCl₃) 136.67, 137.11, 115.92,108.07, 60.58, 56.05.

Example 113a,7a-(Dihydro-benzo[b]thiophen-3-yl)-[1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methanol(221)

A solution of 3-bromo-benzo[b]thiophene (86.2 μL, 0.659 mmol) in 5 mLanhydrous diethyl ether was cooled to −8° C. and tert-butyl lithium(1.7M in pentane, 775 μL, 1.318 mmol) was added and the mixture wasstirred for 15 minutes at −78° C. and then 2 hours at room temperature.Aldehyde 207, dissolved in 10 mL of ether was added dropwise over 10minutes at −30° C. and the mixture was stirred for 0.5 hours. Thereaction was quenched with dropwise addition of saturated aqueous NH₄Cl.The aqueous layer was extracted with ether (3×10 mL) and the combinedorganic extracts were washed with saturated aqueous NaHCO₃, brine, dried(MgSO₄), and concentrated. The residue was purified by flashchromatography (20% EtOAc-hexanes), followed by preparative TLC (25%EtOAc-hexanes) to yield 221 (18.1 mg, 32%) as a mixture of isomers.Fraction A: ¹H NMR (CDCl₃) δ 1.27 (s, 3H), 1.70-1.92 (m, 3H), 1.97 (m,1H), 2.25-2.5 (m, 3H), 2.74 (d, J=15.2 Hz, 1H), 3.14 (d, J=15.2 Hz, 1H),3.41 (d, J=1.6 Hz, 1H), 5.44 (d, J=5.2 Hz, 1H), 6.13 (d, J=2.0 Hz, 1H),7.16 (t, J=8.4 Hz, 2H), 7.21 (s, 1H), 7.27-7.37 (m, 2H), 7.42-7.50 (m,3H), 7.72 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H); HR-MS calculatedfor C₂₇H₂₅FN₂OS: 444.1672, found: 444.1675. Fraction B: ¹H NMR (CDCl₃) δ1.27 (s, 3H), 1.80-2.10 (m, 4H), 2.20-2.50 (m, 3H), 2.58-2.65 (m, 1H),3.04 (t, J=15.2 Hz, 1H), 3.19 (d, J=15.2 Hz, 1H), 3.41 (d, J=1.6 Hz,2H), 3.63 (d, J=4.4 Hz, 1H), 6.12 (s, 1H), 7.11-7.18 (m, 2H), 7.35-7.48(m, 4H), 7.49 (s, 1H), 7.80 (t, J=5.2 Hz, 2H).

Example 12[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-(3,4,5-trimethoxyphenyl)-methanol(223)

Following the procedure of Example 11 but substituting5-bromo-1,2,3-trimethoxy-benzene for 3-bromo-benzo[b]thiophene gave 223.¹H NMR (CDCl₃) δ 1.26 (s, 3H), 1.60-1.90 (m, 4H), 2.00-2.20 (m, 2H),2.24-2.47 (m, 2H), 2.73 (d, J=15.2 Hz, 1H), 3.20 (d, J=15.2 Hz, 1H),3.80-3.90 (m, 9H), 5.10 (s, 1H), 6.12 (s, 1H), 6.50-6.60 (m, 2H),7.10-7.20 (m, 2H), 7.40-7.50 (m, 2H); ¹³C NMR (CDCl₃); HR-MS calculatedfor C₂₈H₃₁FN₂O₄: 478.2268, found: 478.2261.

Example 134-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-3,5-dimethyl-phenol(227)

Following the procedure of Example 11, but substituting4-bromo-3,5-dimethyl-phenoxy)-triisopropylsilane for3-bromo-benzo[b]thiophene gave the triisopropylsilyl ether of4-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-3,5-dimethyl-phenol225. The silyl ether 225 (118.2 mg, 0.201 mmol) was dissolved in 2.5 mLTHF and cooled to −78° C. Tetrabutylammonium fluoride (1M in THF, 273μL, 0.273 mmol) was added dropwise and the solution stirred for 15minutes. The reaction was quenched with 5 mL H₂O. The aqueous phase wasextracted with ether (4×5 mL) and the pooled organic extracts werewashed with brine, dried (MgSO₄), and concentrated. The residue waspurified by flash chromatography over silica gel (0-2% MeOH—CHCl₃) andthen the off-white solid product was washed with methanol to yield 227(56 mg, 64%) as a white solid. ¹H NMR (DMSO) δ 1.20 (s, 3H), 1.50-1.80(m, 4H), 2.34 (s, 6H), 2.61 (d, J=15.2 Hz, 1H), 2.94 (d, J=15.2 Hz, 1H),4.0 (s, 2.5H) 5.26 (d, J=2.8 Hz, 1H), 6.15 (s, 1H), 6.38 (s, 2H), 7.32(t, J=8.8 Hz), 7.43 (s, 1H), 7.51 (t, J=4.8 Hz, 2H); ¹³C NMR (DMSO)161.96, 159.54, 154.92, 151.55, 137.86, 136.32, 135.87, 132.34, 125.24,125.16, 116.34, 116.11, 113.86, 108.29, 69.66, 52.89, 33.25, 32.55,25.99, 22.47, 21.79, 19.75.

Example 144-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-keto-methyl}-3,5-dimethyl-phenol(228)

The triisopropylsilyl ether of4-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-3,5-dimethyl-phenol(100 mg, 0.17 mmol) was dissolved in 8 mL CH₂Cl₂. Pyridiniumchlorochromate (55 mg, 0.255 mmol) was added to the solution, which wasstirred for 4.5 hours at room temperature under argon. 20 mL diethylether was added to the mixture and volatiles were removed under vacuum.The residue was purified by flash chromatography (10% EtOAc-hexanes) toyield the silyl ether of 1 (58.7 mg, 59%) of a clear oil. This oil (58.7mg, 0.10 mmol) was dissolved in 6 mL THF and cooled to −78° C.Tetrabutylammonium fluoride (1M in THF, 140 μL, 0.14 mmol) was addeddropwise and the solution stirred for 15 minutes. The reaction wasquenched with 5 mL H₂O. The aqueous phase was extracted with ether (4×5mL) and the pooled organic extracts were washed with brine, dried(MgSO₄), and concentrated. The residue was purified by flashchromatography over silica gel (10-20% ethyl acetate-benzene) to yield228 (45 mg, 100%). ¹H NMR (CDCl₃) δ 1.31 (s, 3H) 1.41 (m, 1H) 1.87 (m,3H) 2.23 (s, 6H) 2.31 (d, J=15.14 Hz, 1H) 2.43 (m, 1H) 2.62 (d, J=16.11Hz, 1H) 3.04 (m, 1H) 3.15 (d, J=15.63 Hz, 1H) 6.12 (s, 1H) 6.44 (s, 2H)7.14 (t, J=8.55 Hz, 2H) 7.36 (s, 1H) 7.39 (s, 1H) 7.43 (dd, J=8.79, 4.88Hz, 2H); ¹³C NMR (CDCl₃) 18.33, 20.48, 25.30, 26.11, 32.48, 33.76,41.81, 61.53, 109.41, 113.94, 115.36, 116.04, 116.27, 125.57, 125.66,128.32, 134.57, 135.35, 135.38, 135.91, 136.76, 137.79, 149.43, 156.49,160.39, 210.97.

Example 154-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methyl}-3,5-dimethyl-phenol(230)

The triisopropylsilyl ether of4-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-3,5-dimethyl-phenol(20 mg, 0.034 mmol) was dissolved in 3 mL CH₂Cl₂ and cooled to −78° C.Triethylsilane (16 μL, 0.102 mmol) and boron trifluoride-etherate (19μL, 0.153 mmol) were added and the solution was stirred for 6 h at roomtemperature under an argon atmosphere. The reaction was quenched with 2mL saturated aqueous sodium bicarbonate and extracted with ether (4×5mL), dried (MgSO₄), and concentrated to yield 23.3 mg of a white solid.The silyl ether of 230 was then deprotected following the procedure ofExample 14 to yield 230 (16.2 mg, 95%). ¹H NMR (CDCl₃) δ 1.04 (s, 3H)1.10 (d, J=12.70 Hz, 1H) 1.16 (m, 1H) 1.30 (m, 2H) 1.67 (m, 2H) 2.21 (d,J=5.37 Hz, 6H) 2.29 (m, 1H) 2.48 (m, 1H) 2.70 (m, 2H) 3.07 (d, J=15.14Hz, 1H) 4.94 (s, 1H) 6.06 (d, J=1.95 Hz, 1H) 6.44 (s, 2H) 7.08 (t,J=8.55 Hz, 2H) 7.39 (m, 3H); ¹³C NMR (CDCl₃) 12.29, 12.70, 17.42, 17.70,17.98, 20.90, 26.23, 26.66, 28.61, 33.39, 33.80, 41.63, 48.96, 109.19,114.09, 115.11, 115.94, 116.16, 125.40, 125.48, 128.32, 129.57, 135.76,137.01, 137.93, 138.24, 138.37, 150.74, 153.41, 160.26, 162.71.

Example 164-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methoxymethoxy-methyl}-3,5-dimethyl-phenol(232)

The triisopropylsilyl ether of4-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-3,5-dimethyl-phenol(50 mg, 0.085 mmol) was dissolved in 10 mL CH₂Cl₂. Diisopropylethylamine(222 μL, 1.275 mmol) and methoxylmethyl chloride (65 μL, 0.850 mmol)were added and the solution was stirred at room temperature for 10 h.The mixture was diluted with 30 mL ethyl acetate. The organic phase waswashed with brine, dried (Na₂SO₄), and concentrated to yield 96.3 mg ofthe silyl ether of 232. This was then deprotected following theprocedure of Example 14 to yield 232 (12.4 mg, 59%). ¹H NMR (CDCl₃) δ1.20 (s, 3H) 1.29 (m, 2H) 1.63 (m, 2H) 1.89 (d, J=13.18 Hz, 1H) 2.14 (m,2H) 2.28 (d, J=14.65 Hz, 1H) 2.36 (s, 3H) 2.39 (s, 3H) 2.55 (m, 1H) 3.39(s, 2H) 4.43 (s, 2H) 5.11 (d, J=6.35 Hz, 1H) 6.08 (s, 1H) 6.31 (m, 1H)6.47 (s, 2H) 7.13 (t, J=7.81 Hz, 2H) 7.36 (d, J=1.95 Hz, 2H) 7.43 (dd,J=6.84, 4.88 Hz, 2H); ¹³C NMR (CDCl₃) 19.30, 21.22, 21.58, 24.29, 26.24,33.23, 33.33, 42.16, 52.01, 56.32, 74.08, 93.81, 108.73, 114.12, 115.40,115.96, 116.19, 117.31, 125.35, 125.43, 128.33, 129.41, 135.62, 135.65,136.78, 137.88, 138.41, 139.84, 151.68, 154.70, 160.25, 162.71.

Example 17 Binding data for compounds 227, 228, 230 and 232

Representative results of glucocorticoid receptor (GR) binding data for4-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methyl}-3,5-dimethyl-phenoland certain derivatives are shown in Table 1, compared to dexamethasone.

TABLE 1 GR Binding RBA GR Compound (dexamethasone = 100) pot(EC50, nM)227 50 125 228 16 — 230 22 — 232 26  82 dexamethasone 100 2.2 ± 0.1

Example 183-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-phenol(229)

Following the procedure of Example 11 but substituting3-bromo-phenoxy-triisopropylsilane for 3-bromo-benzo[b]thiophene gavethe triisopropylsilyl ether of3-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-phenol229, which was then deprotected following the procedure of Example 13.¹H NMR (CDCl₃) δ 1.14 (s, 5H), 1.18-1.30 (m, 7H), 1.36 (s, 1H), 1.5-1.7(m, 5H), 1.8-1.95 (m, 2H), 2.20-2.32 (m, 3H), 2.60 (d, J=15.9 Hz, 0.5H),2.71 (d, J=15.4 Hz, 0.5H), 2.78 (d, J=16.2 Hz, 1H), 2.98 (s, 1H), 3.17(t, J=15.6 Hz, 1H), 3.65 (d, J=16.2 Hz, 1H), 4.56 (d, J=8.9 Hz, 1H),4.99 (s, 0.5H), 5.09 (s, 0.5H), 6.09 (s, 0.3H), 6.11 (s, 0.3H), 6.13 (s,1H), 6.15 (s, 0.4H), 6.7-6.9 (m, 6H), 7.1-7.22 (m, 5H), 7.4-7.5 (m, 5H);¹³C NMR (CDCl₃) 162.68, 160.22, 156.34, 155.97, 151.06, 147.46, 146.72,138.20, 137.89, 137.44, 136.78, 135.61, 129.68, 129.58, 129.48, 125.38,125.30, 125.26, 125.18, 119.34, 117.67, 116.30, 116.16, 115.93, 115.45,115.04, 114.72, 114.05, 113.73, 112.72, 109.53, 109.46, 72.40, 71.91,65.86, 56.53, 53.94, 50.70, 49.39, 41.52, 41.46, 41.29, 40.89, 35.79,33.83, 30.30, 28.70, 27.57, 27.07, 25.34, 25.16, 23.59, 22.64, 21.33,20.58, 17.84, 17.67, 15.22.

Example 194-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-phenol(231)

Following the procedure of Example 11 but substituting4-bromo-phenoxy)-triisopropylsilane for 3-bromo-benzo[b]thiophene gavethe triisopropylsilyl ether of4-{[1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-phenol231 which was then deprotected following the procedure of Example 13. ¹HNMR (MeOD) δ 1.00-1.13 (m, 12H), 1.24 (s, 3H), 1.26-1.40 (m, 3H),1.55-2.00 (m, 7H), 2.25-2.50 (m, 4H), 2.65-2.80 (m, 2H), 3.20 (d, J=15.9Hz, 1H), 3.65 (d, J=15.9 Hz, 1H), 5.07 (s, 1H), 5.48 (s, 0.5H),6.07-6.17 (m, 1.5H), 6.71-6.80 (m, 2H), 7.17 (j, J=8.6 Hz, 3H), 7.26 (t,J=8.6 Hz, 3H), 7.39-7.49 (m, 4H); ¹³C NMR (CDCl₃) 162.66, 160.20,150.74, 149.99, 149.94, 144.08, 143.27, 138.26, 138.03, 137.99, 137.17,136.71, 136.43, 135.82, 130.10, 129.97, 129.49, 125.66, 125.37, 125.29,125.23, 125.14, 124.40, 124.33, 116.13, 116.09, 115.89, 115.87, 115.22,114.65, 114.04, 109.83, 109.62, 109.28, 105.72, 105.42, 71.22, 69.29,56.86, 55.24, 53.84, 48.85, 41.60, 41.58, 41.20, 35.71, 34.67, 33.69,33.36, 27.69, 25.96, 25.63, 25.32, 23.74, 21.43, 20.58, 20.02, 18.09,17.77.

Example 204-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-2-methyl-phenol(235)

Following the procedure of Example 11 but substituting(4-bromo-2-methyl-phenoxy)-triisopropylsilane for3-bromo-benzo[b]thiophene gave the triisopropylsilyl ether of4-{[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-hydroxy-methyl}-2-methyl-phenol 233 which was thendeprotected following the procedure of Example 13 to provide 235 in 25%yield. ¹H NMR (CDCl₃) δ 1.25 (3H), 1.50-1.80 (m, 6H), 2.26 (s, 3H),2.27-2.47 (m, 2H), 2.73 (d, J=15.2 Hz, 1H), 3.16 (d, J=15.2 Hz, 1H),5.10 (s, 1H), 6.10 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz,1H), 7.07 (s, 1H), 7.14 (t, J=8.0 Hz, 2H), 7.40-7.50 (m, 3H). ¹³C NMR(CDCl₃) 158.97, 149.16, 146.84, 134.20, 133.86, 124.28, 121.70, 121.62,120.18, 119.94, 112.41, 112.18, 110.88, 110.17, 105.31, 68.02, 52.95,47.28, 37.53, 31.34, 29.64, 27.18, 22.04, 16.24, 16.15, 12.22.

Example 21[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-(1H-indol-4-yl)-methanol(14%) (237)

Following the procedure of Example 11 but substituting 5-bromoindole for3-bromo-benzo[b]thiophene gave (237) in 14% yield. ¹H NMR (CDCl₃) δ 1.26(s, 3H), 1.50-1.80 (m, 4H), 2.10-2.50 (m, 3H), 2.77 (d, J=15.2 Hz, 1H),3.16 (d, J=15.2 Hz, 1H), 5.24 (d, J=2.4 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H),6.53 (s, 1H), 7.14-7.22 (m, 4H), 7.32 (d, J=8.4 Hz, 1H), 7.40-7.50 (m,3H), 7.64 (s, 1H), 8.52 (s, 1H); ¹³C NMR (CDCl₃) 150.82, 137.92, 137.21,136.94, 134.86, 127.61, 125.34, 125.26, 124.73, 119.87, 117.04, 116.07,115.84, 115.80, 114.01, 110.76, 108.87, 102.41, 72.33, 60.37, 56.90,41.29, 34.97, 33.89, 25.77, 19.94, 19.79, 14.13.

Example 22[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-thiophen-3-yl-methanol(238)

Following the procedure of Example 11 but substituting 3-bromothiophenefor 3-bromo-benzo[b]thiophene gave (238) in 20% yield as a mixture ofisomers. ¹H NMR (CDCl₃) δ 1.22 (s, 3H), 1.70-1.94 (m, 4H), 2.24-2.48 (m,2H), 2.96 (d, J=15.3 Hz, 1H), 2.99 (s, 1H), 3.13 (d, J=15.3 Hz, 1H),5.42 (d, J=3.7 Hz, 1H), 6.10 (d, J=2.3 Hz, 1H), 6.93 (d, J=5.2 Hz, 1H),7.14 (m, 2H), 7.22 (d, J=5.2 Hz, 1H), 7.40-7.46 (m, 3H); ¹³C NMR (CDCl₃)150.21, 144.41, 137.94, 136.77, 135.75, 130.04, 125.39, 125.30, 124.25,116.12, 115.89, 114.03, 109.15, 105.18, 69.09, 53.76, 41.58, 34.60,33.26, 25.63, 20.57, 20.01.

Example 234a′-methyl-(4′H,5′H,7′H)-spiro[1,3-dithiolane-2,2′-naphthalen]-5′(6′H)-one(239)

To a solution of Wieland-Miescher ketone (5.87 g, 33.0 mmol) in glacialacetic acid (40 mL) was added p-toluenesulfonic acid (2.94 g) followedby dropwise addition of 1,2-ethanedithiol over a 1 hour period. Thereaction mixture was stirred at room temperature for another 4 hours,poured into 30 mL water, and stirred for 15 minutes. The white solid wasfiltered off, washed successively with water, diluted with NaHCO₃solution and water, and then dried to yield thioketal 239 (7.33 g,87.3%) as a white solid. ¹H NMR (CDCl₃) δ 1.50-2.70 (m, 10H), 3.20-3.40(m, 4H), 5.67 (s, 1H); ¹³C NMR (CDCl₃) 212.92, 141.23, 128.04, 64.81,49.43, 40.11, 39.62, 37.92, 37.57, 30.81, 30.69, 24.73, 24.57.

Example 244a′-methyl-(4′H,5′H,7′H)-spiro[1,3-dithiolane-2,2′-naphthalen]-5′-carboxaldehyde(241)

To a cold (−30° C.) solution of (methoxymethyl)triphenylphosphoniumchloride (6.753 g, 19.7 mmol) in THF (40 mL), was added KHMDS (0.5M intoluene, 35.46 mL, 17.73 mmol). The resulting red solution was stirredat 0° C. for 15 minutes before being treated with a solution of 241 (1g, 3.94 mmol) in THF (10 mL). The mixture was stirred at roomtemperature for 24 hours. A solution of methanol in THF (1:1, 12 mL) and4 N HCl (13 mL) was added to the reaction mixture at 0° C. The resultingsolution was allowed to stir at room temperature for 36 hours, pouredinto water (40 mL) and extracted with ether (4×30 mL). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated.Purification of the residue by flash chromatography on silica gel (1-3%ethyl acetate-hexanes) gave 783 mg (74%) of 241. ¹H NMR (CDCl₃) δ 1.14(s, 3H), 1.25-2.4 (m, 11H), 3.20-3.45 (m, 4H), 5.52 (s, 1H), 9.81 (d,J=2.0 Hz, 1H); ¹³C NMR (CDCl₃) 200.71, 139.59, 122.18, 61.37, 56.86,36.40, 35.88, 33.56, 33.46, 33.06, 27.99, 22.15, 18.36, 15.84.

Example 25{4a′-methyl-(4′H,5′H,7′H)-spiro[1,3-dithiolane-2,2′-naphthalen]-5′yl}-(3,4,5-trimethoxy-phenyl)-methanol(243)

A solution 5-bromo-1,2,3-trimethoxy-benzene (276 mg, 1.12 mmol)dissolved in 6 mL anhydrous ether is cooled to −78° C. andtert-butyllithium (1.7 M in pentane, 1.32 mL, 2.24 mmol) is added. Themixture was stirred at −78° C. for 15 minutes, then at room temperaturefor 3 hours. Aldehyde 241 (100 mg, 0.373 mmol) was added dropwise over10 minutes in 10 mL ether at −30° C. The mixture was stirred for 0.5hours and the reaction quenched with dropwise addition of saturatedaqueous NH₄ ⁺Cl⁻. The phases were separated and the aqueous phase wasextracted with ether (4×10 mL). The pooled organic extracts were washedwith saturated aqueous NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated under vacuum. The residue was purified by flashchromatography over silica gel (25% ethyl acetate-hexanes) to yield 243(119 mg, 73%).

Example 26{4a′-methyl-(4′H,5′H,7′H)-spiro[1,3-dithiolane-2,2′-naphthalen]-5′yl}-(3-triisopropylhydroxyphenyl)-methanol(245)

Following the procedure of Example 25 but substituting3-bromo-phenoxy)-triisopropyl-silane for5-bromo-1,2,3-trimethoxy-benzene provided the triisopropyl derivative of{4a′-methyl-(4′H,5′H,7′H)-spiro [1,3-dithiolane-2,2′-naphthalen]-5′yl}-(3-triisopropylhydroxyphenyl)-methanol 245.

Example 27(3a,7a-Dihydro-benzo[b]thiophen-3-yl)-{4a′-methyl-(4′H,5′H,7′H)-spiro[1,3-dithiolane-2,2′-naphthalen]-5′yl}-methanol(249)

Following the procedure of Example 26 but substituting3-bromo-benzo[b]thiophene for 5-bromo-1,2,3-trimethoxy-benzene provided249 in 54% yield.

Example 28{4a′-methyl-(4′H,5′H,7′TH)-spiro[1,3-dithiolane-2,2′-naphthalen]-5′yl}-phenyl-methanol(247)

Aldehyde 241 (200 mg, 0.746 mmol) was dissolved in 10 mL THF and cooledto −78° C. Phenylmagnesium bromide (1M in THF, 1.12 mL, 1.12 mmol) wasadded to the solution dropwise and the mixture was allowed to warm toroom temperature over 2 hours. The reaction mixture was then cooled to0° C. and quenched with 10 mL of water. The layers were separated andthe aqueous layer was extracted with (3×10 mL) ether. The pooled organicextracts was washed with brine, dried (MgSO₄), filtered, andconcentrated under vacuum. Purification by flash chromatography oversilica gel (10% ethyl acetate-hexanes) afforded alcohol 247 (240 mg,93%) as a white solid.

Example 295-(Hydroxy-phenyl-methyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one(251)

Thioketal 245 (100 mg, 0.288 mmol) was dissolved in 3 mL CHCl₃ and 1 mLMeOH. A solution of Hg(ClO₄)₂ (253 mg, 0.633 mmol) in 3 mL MeOH wasadded dropwise. After 5 minutes of stirring at room temperature, themixture was filtered and the filtrate was neutralized with 5 mLsaturated NaHCO₃ solution. The layers were separated and the organiclayer was extracted with CHCl₃ (3×5 ml). The pooled organic extractswere dried (MgSO₄) and filtered over a pad of alumina and celite. Thefiltrate was washed with CH₂Cl₂ and the solvents evaporated under vacuumto yield 251 (78 mg, 73%) as a white solid. ¹H NMR (CDCl₃) δ 1.42 (s,3H), 1.50-2.60 (m, 11H), 5.13 (d, J=4.0 Hz, 1H), 5.70 (s, 1H), 7.20-7.40(m, 5H); ¹³C NMR (CDCl₃); HR-MS calculated for C₁₈H₂₂O₂: 270.1619,found: 270.1621.

Example 305-[Hydroxy-(3,4,5-trimethoxy-phenyl)-methyl]-4a-methyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one(253)

Following the procedure of Example 29 but substituting thioketal 243 forthioketal 245 provided ketone 253 in 87% yield. ¹H NMR (CDCl₃) δ 1.43(s, 3H), 1.50-2.70 (m, 11H), 3.83 (s, 3H), 3.86 (s, 6H), 5.07 (s, 1H),5.73 (s, 1H), 6.50 (s, 2H); ¹³C NMR (CDCl₃) 195.66, 167.64, 149.51,149.36, 137.56, 132.95, 120.19, 99.99, 98.56, 67.52, 57.09, 52.40,52.27, 35.89, 32.56, 30.15, 29.76, 22.42, 15.67, 15.03; HR-MS calculatedfor C₂₁H₂₈O₅: 360.1936, found: 360.1935.

Example 315-[(3a,7a-Dihydro-benzo[b]thiophen-3-yl)-hydroxy-methyl]-4a-methyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one(255)

Following the procedure of Example 29 but substituting thioketal 249 forthioketal 245 provided ketone 255 in 87% yield. ¹H NMR (CDCl₃) δ 1.43(s, 3H), 1.70-2.00 (m, 6H), 2.15 (d, J=5.6 Hz, 1H), 2.20-2.65 (m, 7H),5.41 (d, J=5.2 Hz, 1H), 5.76 (s, 1H), 7.18 (s, 1H), 7.27-7.40 (m, 2H),7.76 (d, J=7.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H); ¹³C NMR (CDCl₃); HR-MScalculated for C₂₀H₂₂O₂S: 326.1341, found: 326.1348.

Example 325-[Hydroxy-(3-hydroxy-phenyl)-methyl]-4a-methyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one:84% (257)

Following the procedure of Example 29 but substituting thioketal 247 forthioketal 245 and then following the procedure of Example 13 gave 257(53.8 mg, 84%) as a white solid. ¹H NMR (CDCl₃) δ 1.36 (s, 3H),1.40-2.80 (m, 12H), 5.01 (d, J=2.0 Hz, 1H), 5.70 (s, 1H), 6.60-6.90 (m,2H), 7.15 (t, J=8.0 Hz, 1H), 7.62 (s, 1H); ¹³C NMR (CDCl₃); HR-MScalculated for C₁₈H₂₂O₃: 286.1569, found: 286.1570.

Example 33[1-(4-Fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-phenanthren-9-yl-methanol(259)

Following the procedure of Example 11 but substituting9-bromophenanthrene for 3-bromo-benzo[b]thiophene gave (259) in 32%yield. ¹H NMR (CDCl₃) δ 1.41 (s, 3H) 1.80 (m, 4H) 1.95 (d, J=11.72 Hz,1H) 2.27 (m, 1H) 2.42 (m, 1H) 3.13 (d, J=14.65 Hz, 1H) 3.45 (d, J=14.65Hz, 1H) 6.03 (d, J=2.93 Hz, 1H) 6.12 (d, J=1.95 Hz, 1H) 7.15 (t, J=8.79Hz, 2H) 7.47 (dd, J=9.03, 4.64 Hz, 2H) 7.59 (s, 1H) 7.65 (m, 4H) 7.94(d, J=7.32 Hz, 1H) 8.02 (s, 1H) 8.08 (d, J=7.81 Hz, 1H) 8.68 (d, J=7.81Hz, 1H) 8.78 (d, J=6.84 Hz, 1H); ¹³C NMR (CDCl₃) 20.31, 20.38, 25.66,33.32, 34.75, 42.62, 52.26, 69.15, 108.97, 113.82, 115.92, 116.14,122.41, 123.27, 123.56, 125.01, 125.26, 125.34, 126.24, 126.61, 126.64,126.84, 128.79, 129.24, 129.85, 130.74, 131.12, 135.84, 136.94, 137.97,138.1, 151.08, 160.19.

Example 344a-Methyl-1-(3-phenylethynyl-phenyl)-1,4,4a,6,7,8-hexahydro-benzo[f]indazol-5-one(261)

Following the procedure of Example 3 but substituting(3-Phenylethynyl-phenyl)-hydrazine hydrochloride for4-fluorophenylhydrazine hydrochloride gave (261) in 26% yield over twosteps. ¹H NMR (CDCl₃) δ 1.25 (s, 3H) 1.68 (m, 1H) 2.08 (m, 1H) 2.61 (m,4H) 2.90 (d, J=2.93 Hz, 2H) 6.38 (d, J=1.47 Hz, 1H) 7.35 (m, 3H) 7.46(m, 2H) 7.49 (s, 1H) 7.51 (s, 1H) 7.54 (dd, J=6.59, 3.17 Hz, 2H) 7.66(s, 1H); ¹³C NMR (CDCl₃) 22.6, 23.2, 28.2, 31.5, 38.5, 50.6, 88.3, 90.3,110.9, 114.3, 122.7, 123.2, 124.4, 126.2, 128.3, 128.5, 129.2, 130.1,131.5, 135.8, 138.6, 139.6, 145.7, 212.5.

Compound 261 gave an IC50 of 174.4 nM in a GR binding assay.

Example 353-(4-fluoro-phenyl)-8-bromo-11b-methyl-5,6,12-trihydro-indazolo[5,6-a]carbazole(263)

Following the procedure of Example 3 but substituting4-bromo-phenylhydrazine hydrochloride for 4-fluorophenylhydrazinehydrochloride gave 263 in 24% yield. ¹H NMR (CDCl₃) δ 1.37 (s, 3H) 2.65(m, 3H) 2.79 (d, J=15.63 Hz, 1H) 2.94 (dd, J=13.18, 3.91 Hz, 1H) 3.00(d, J=15.14 Hz, 1H) 6.40 (s, 1H) 7.14 (d, J=3.42 Hz, 1H) 7.17 (d, J=3.42Hz, 1H) 7.22 (m, 1H) 7.36 (s, 1H) 7.49 (m, 3H) 7.61 (d, J=1.95 Hz, 1H)8.28 (s, 1H); ¹³C NMR (CDCl₃) 21.7, 24.7, 31.1, 33.4, 37.7, 108.8,110.7, 112.1, 112.5, 114.4, 116.1, 116.3, 121.0, 124.2, 125.4, 125.4,128.3, 128.6, 134.9, 135.5, 137.1, 137.9, 141.6, 147.5.

Example 363-(4-fluoro-phenyl)-8-methoxy-11b-methyl-5,6,12-trihydro-indazolo[5,6-a]carbazole(265)

Following the procedure of Example 3 but substituting4-methoxy-phenylhydrazine hydrochloride for 4-fluorophenylhydrazinehydrochloride gave (265) in 16.8% yield. ¹H NMR (CDCl₃) δ 1.39 (s, 3H)2.69 (m, 3H) 2.82 (d, J=15.14 Hz, 1H) 2.99 (m, 2H) 3.86 (s, 3H) 6.41 (s,1H) 6.83 (dd, J=8.79, 2.44 Hz, 1H) 6.96 (d, J=2.44 Hz, 1H) 7.18 (m, 2H)7.22 (d, J=8.79 Hz, 1H) 7.51 (m, 3H) 7.88 (s, 1H); ¹³C NMR (CDCl₃) 22.0,24.8, 31.3, 33.6, 37.7, 56.0, 100.8, 109.1, 110.6, 111.4,114.6, 116.0,116.2, 125.3, 125.3, 127.2, 128.3, 131.3, 135.7, 135.8, 137.1, 138.0,141.2, 147.9, 154.1, 160.3, 162.8.

Example 373-(4-fluoro-phenyl)-8-fluoro-11b-methyl-5,6,12-trihydro-indazolo[5,6-a]carbazole(267)

In a 50 mL round bottom flask fitted with a Dean-Stark trap andcondensor, a mixture of ketone (205) (150 mg, 0.51 mmol),4-fluorophenylhydrazine hydrochloride (91 mg, 0.56 mmol), and sodiumacetate (46 mg, 0.56 mmol), were dissolved in 10 mL glacial acetic acidand heated to 100° C. for 3 h. After cooling to room temperature,solvents were evaporated and the residue was purified by flashchromatography (30% EtOAc/benzene) to yield (269) (67.8 mg, 34%). ¹H NMR(CDCl₃) δ 1.40 (s, 3H) 2.67 (m, 3H) 2.84 (d, J=15.14 Hz, 1H) 2.95 (t,J=4.88 Hz, 1H) 3.03 (d, J=15.14 Hz, 1H) 6.42 (s, 1H) 6.91 (td, J=9.16,2.69 Hz, 1H) 7.13 (dd, J=9.77, 2.44 Hz, 1H) 7.19 (t, J=8.30 Hz, 2H) 7.24(dd, J=8.79, 4.39 Hz, 1H) 7.50 (t, J=4.39 Hz, 2H) 7.53 (s, 1H) 7.93 (s,1H); ¹³C NMR (CDCl₃) 21.9, 24.8, 31.2, 33.6, 37.7, 103.4, 103.6, 109.5,109.5, 109.8, 110.8, 111.2, 111.3, 114.4, 116.0, 116.3, 125.3, 125.4,127.2, 127.3, 132.6, 137.0, 138.0, 142.2, 147.4, 156.7, 159.1, 160.3,162.8.

Example 386-Anthracen-9-ylmethylene-1-(4-fluoro-phenyl)-4a-methyl-1,4,4a,6,7,8-hexahydro-benzo[f]indazol-5-one(269)

In a 100 mL round bottom flask, aldehyde (207) (100 mg, 0.337 mmol) andanthracene-9-carboxaldehyde (349 mg, 1.69 mmol) were dissolved in 10 mLTHF and cooled to 0° C. Lithium hexamethyldisilylamide (LHMDS) (370 μL,0.370 mmol) was added dropwise, and the solution was stirred at roomtemperature for 16 hours. The reaction was quenched with 5 mL ofsaturated aqueous ammonium chloride. The aqueous layer was extractedwith ether (3×10 mL), and the pooled organic extracts were washed withbrine (10 mL), dried (MgSO₄) and then concentrated. Flash chromatographyof the residue (0-25% EtOAc/hexanes) gave (269) (127.9 mg, 78%). ¹H NMR(CDCl₃) δ 1.45 (s, 3H) 2.19 (m, 1H) 2.35 (m, 2H) 2.47 (m, 1H) 3.04 (d,J=16.11 Hz, 1H) 3.15 (d, J=16.11 Hz, 1H) 6.25 (s, 1H) 7.13 (t, J=8.55Hz, 2H) 7.47 (m, 6H) 7.55 (s, 1H) 7.87 (m, 1H) 8.00 (m, 3H) 8.39 (s, 1H)8.43 (s, 1H); ¹³C NMR (CDCl₃) 23.5, 27.2, 29.7, 30.2, 49.4, 110.4,114.0, 115.9, 116.1, 125.0, 125.1, 125.2, 125.3, 125.5, 126.1, 127.5,128.8, 128.9, 128.9, 129.0, 129.7, 131.1, 131.1, 135.5, 135.7, 135.7,136.4, 138.5, 139.1, 145.2, 160.2, 162.6, 202.8.

Example 39 Binding Data for Compounds 263, 265, 267 and 269

Representative results of glucocorticoid receptor (GR) binding data forthe compounds of Examples 35-38 are shown in Table 2, compared todexamethasone.

TABLE 2 GRE Activation GR Repression Coll A Com- GR Binding pot(EC50,Max fold pot(EC50, % max pound (IC50, nM) nM) activation nM) repression263 708 ND ND ND ND 265 239 ND ND ND ND 267 130 — 18 100 75% 26943 >5000 — >5000 — Dexa- 25 3.7 50 0.36 84% methasone

Example 40 Binding Data for Compounds 221, 223, 227, 229, 231, 235, 237,238, and 259

Representative results of glucocorticoid receptor (GR) binding data forthe compounds of Examples 11-13, 18-22, and 33, are shown in Tables 3-5,compared to dexamethasone and other compounds.

TABLE 3 GR binding Example Compound RBA (dex = 100) 11 221 93 12 223 4713 227 103 21 237 110 20 235 110 22 238 14, 39 18 229 52 19 231 36 33259 72 Dexamethasone 100

TABLE 4 GRE activation GR PR MR AR pot (EC50, max fold max fold max foldmax fold Example Compound nM) activation activation activationactivation 11 221 313 21 — 2.0 ± 0.7 — 11 221 ND ND ND 12 223 143 ± 2732 ± 2 — — — 13 227 130 ± 43  95 ± 23 144 ± 32 3.2 ± 0.9  4.6 ± 1.6 21237 149 ± 91  92 ± 18 — 5.0 ± 1.5 — 20 235 81 76 — — — 22 238  251 ± 11886 ± 4 155 ± 32 6.2 ± 0.9 — 22 238 230 ± 80 112 ± 75 109 ± 10 ND — 18229 110 ± 7  55 ± 2 — 3.1 ± 1.0 — 19 231 330 ± 92  69 ± 25 — 2.9 ± 0.5 —33 259 >5000 — ND ND ND Cortisol  78 ± 43 84 ± 2  53 ± 10 25 ± 5  15 ± 5Dexamethasone  2.2 ± 0.01  38 ± 16 ND 30 ± 2  23 ± 2 Aldosterone 765 41ND 6.1 ± 1.5 — Progesterone 255 ± 72 ND ND Dihydro- ND ND 46 ± 7testosterone (DHT)

TABLE 5 Repression AP-1 Coll A NF-KB pot (EC50, % max pot (EC50, % maxpot (EC50, % max Example Compound nM) repression nM) repression nM)repression 11 221 5.3 74% 11 221 ND ND 12 223 6.7 74% 13 227 6 77% 6.975% 21 237 4.9 80% 8.1 75% 26.4 74% 20 235 16.6 74% 22 238 19.1 75% 2768% 22 238 14.7 73% 18 229 16.6 77% 19 231 12.8 68% 28 70% 33 259 ND ND783 73% Cortisol 0.78 90% 2.1 8.4 83% Dexamethasone 0.15 89% 0.36 84%1.5 87%

Example 41 Glucocorticoid Receptor Binding Assay, Tissue Culture,Transfection, and Luciferase Assays

The Glucocorticoid Receptor Competitor Assay Kit (Panvera Corp, Madison,Wis.) was used for ligand binding studies. The recommended roomtemperature protocol was followed for all assayed ligands.

Plasmids for GR (human, pSG5 backbone), AP1-Luc (synthetic AP1 responseelement upstream of a firefly luciferase gene), TAT_(S)-Luc (threecopies of the tyrosine aminotransferase glucocorticoid response elementupstream of a firefly luciferase gene), β-galactosidase (used as atransfection control), as well as two stable transfected cells lines: anA549 (human, lung carcinoma) cell line stably tansfected with a KBresponse element upstream of a firefly luciferase gene, (R. M. Nissen etal., Genes Dev., 14(18):2314-29, (2000)) and a U2OS (human,osteosarcoma) stably transfected with rat GR (I. Rogatsky, et al., Mol.Cell. Biol., 1997, 17, 3181-3193) were a gift of Professor KeithYamamoto (Department of Biochemistry, University of California, SanFrancisco).

For TAT₃ activation assays, CV-1 cells were grown in 0.1 μm filtered DMEsupplemented with 4.5 g/L glucose, 0.584 g/L L-glutamine, 3.7 g/LNaHCO₃, 100 mg/L streptomycin sulfate, 100 units/ml of penicillin G and5% fetal bovine serum. Cells were plated into tissue culture treated, 96well flat bottom plates (25,000 cells/well), and incubated for 12 h at37° C. Cells were then transfected using the Lipofectamine PLUStransfection reagent (Gibco BRL). DNA-lipid complexes of 5 ng GR, 50 ngTAT₃-Luc, 7.5 ng β-galactosidase, 1 μL/well PLUS reagent and 0.67μL/well lipofectamine in 50 μL/well serum free media were added to cellsand incubated for 4 h at 37° C. Complexes were removed and hormonesdiluted in 5% charcoal-stripped FBS were added to the cells, which werethen incubated for 24 hours at 37° C. Media was removed and the cellswere washed with 100 μL Ca⁺², Mg⁺² free phosphate buffered saline (PBS).Lysis was achieved by adding 50 μL of Passive Lysis Buffer (PromegaCorp, Madison, Wis.) and shaking the plate for 15 min. 15 μL of thislysate was then used to assay β-galactosidase activity (β-galactosidaseenzyme assay system, Promega Corp., recommended procedures followed).The Luciferase Assay System (Promega Corp.) was used to assay luciferaseactivity. 100 μL of luciferase assay reagent was added rapidly to theplate and luminescence was measured for 10 ms/well on an Analyst ADDetection System (LJL Biosystems, Sunnyvale, Calif.).

For AP1 repression assays, U2OS cells stably transfected with rat GRwere grown in similar media as for CV-1 cells with the exception of theFBS concentration, which was 10% and the only antibiotic was 350 μg/mL.Cells were plated and transfected in a similar fashion, except forplasmids, which in this case were 50 ng/well AP1-Luc and 10 ng/wellβ-galactosidase. Post-transfection, cells were incubated with either 50ng/mL TPA (Phorbol 12-myristate 13-acetate), or 50 ng/mL TPA and varioushormone dilutions in 10% charcoal treated FBS media. The cells wereincubated for 12 h, and the lysis, β-galactosidase assay, and luciferaseassay were performed as previously described.

For NF-κB repression assays, A549 cells stably transfected with aluciferase reporter were grown under the same conditions as CV-1 cells.50,000 cells/well were plated into 96 well plates and incubated for 12 hat 37° C. Either TNF-α alone or mixed with various hormone dilutions inmedia were then added to the cells, which were then incubated for 8hours. Procedures for lysis and luciferase assay were performed aspreviously described. Protein content was used as a control in this caseand the recommended procedures using the BCA Protein Assay Kit (Roche)were followed.

The compounds of the invention possessed significant binding affinityfor the glucocorticoid receptor (greater than 1.0 μm). Thetransactivation data indicated that the compounds of the invention wereable to selectively disassociate the different response elements of theglucocorticoid receptor.

Finally, it should be noted that there are alternative ways ofimplementing both the present invention. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the invention is not to be limited to the details given herein, butmay be modified within the scope and equivalents of the appended claims.

All patents and other publications cited herein are incorporated hereinby reference in their entirety for all purposes.

1. A compound according to the structural formula:

or a pharmaceutically available salt, solvate, or hydrate thereofwherein: A, B and C are independently carbon, nitrogen, oxygen or sulfurprovided that at least one of A, B and C is nitrogen, oxygen or sulfurand that no more than one of A, B and C are oxygen or sulfur; W iscarbon, oxygen, nitrogen, or sulfur and, when W is other than carbon andnitrogen, one or more of R₈, R₉ and R₁₀ is absent so that a normalvalence on W is maintained; R₁ is hydrogen, alkyl, substituted alkyl,acyl, substituted acyl, acylamino, substituted acylamino, amino,alkylamino, substituted alkylamino, dialkylamino, substituteddialkylamino, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl,substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl,carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl orsubstituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl;R₂, R₃, R₅, R₆, R₆′ and R₇ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, acylamino, substitutedacylamino, alkoxy, substituted alkoxy, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl,substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl,alkylthio, substituted alkylthio, alkoxycarbonyl, substitutedalkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl,substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy,cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl,substituted heteroarylalkyl or hydroxy; R₂′, R₃′, R₅′, R₇′ and R₈ areabsent or are independently hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, acylamino, substituted acylamino, alkoxy, substitutedalkoxy, amino, alkylamino, substituted alkylamino, dialkylamino,substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl,alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl,substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl,carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl,substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl orhydroxy; R₄ is absent or is hydrogen, alkyl, substituted alkyl, acyl,substituted acyl, acylamino, substituted acylamino, amino, alkylamino,substituted alkylamino, dialkylamino, substituted dialkylamino,alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substitutedarylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl,substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substitutedheteroalkyl, heteroarylalkyl or substituted heteroarylalkyl; R₉ ishydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,alkylamino, substituted alkylamino, dialkylamino, substituteddialkylamino, carboxy, cyano, halo, oxo, thio, hydroxy or is absent; andR₁₀ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, aryloxycarbonyl, substitutedaryloxycarbonyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl or is absent; R₁₀ and R₂ may bond directly to oneanother to form a ring, and an additional ring, which may itself besubstituted with an alkyl, alkoxy, halo, alkyl, substituted alkyl, acyl,substituted acyl, cycloalkyl, or substituted cycloalkyl, may fuse to thebond between R₁₀ and R₂; R₁₁ and R₁₂ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, acylamino, substitutedacylamino, alkoxy, substituted alkoxy, amino, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl,substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl,alkylthio, substituted alkylthio, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl,substituted carbamoyl, carboxy, cyano, halo, oxo, thio, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl or hydroxy; and one of thebonds in formula (I) that are shown with single and dashed lines is adouble bond provided that normal valences of the atoms in the rings aresatisfied.
 2. The compound of claim 1, wherein A, B and C are carbon ornitrogen.
 3. The compound of claim 2, wherein A is carbon and B and Care nitrogen.
 4. The compound of claim 1, wherein A, B and C are carbon,nitrogen or sulfur.
 5. The compound of claim 4, wherein A is sulfur, Bis carbon and C is nitrogen.
 6. The compound of claim 1, wherein A, Band C are carbon, nitrogen or oxygen.
 7. The compound of claim 6,wherein A is carbon, B is oxygen and C is nitrogen.
 8. The compound ofclaim 6, wherein A is carbon, B is nitrogen and C is oxygen.
 9. Thecompound of claim 1, wherein R₁ and R₄ are independently hydrogen,alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl,substituted alkoxycarbonyl, carboxy, cyano, carbamoyl, substitutedcarbamoyl, heteroalkyl and substituted heteroarylalkyl.
 10. The compoundof claim 1, wherein R₁ and R₄ are independently hydrogen, alkanyl orsubstituted alkanyl.
 11. The compound of claim 1, wherein R₁ and R₄ areindependently hydrogen or methyl.
 12. The compound of claim 1, whereinR₂, R₃, R₅, R₆, R₆′, and R₇ are independently hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, alkoxy, substituted alkoxy,amino, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl,substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substitutedheteroalkyl, or hydroxy.
 13. The compound of claim 1, wherein R₂, R₂′,R₃, R₅, R₆, R₆′, R₇ and R₈ are independently hydrogen, alkanyl orsubstituted alkanyl.
 14. The compound of claim 1, wherein R₂, R₂′, R₃,R₅, R₆, R₆′, R₇ and R₈ are hydrogen or methyl.
 15. The compound of claim1, wherein R₄ and R₅′ are absent.
 16. The compound of claim 1, whereinR₄ and R₇′ are absent.
 17. The compound of claim 1, wherein R₃′ and R₇′are absent.
 18. The compound of claim 1, wherein R₃′, R₅′ and R₇′ areindependently hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, alkoxy, substituted alkoxy, amino, alkoxycarbonyl, substitutedalkoxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo,heteroalkyl, substituted heteroalkyl, or hydroxy.
 19. The compound ofclaim 1, wherein R₃′, R₅′ and R₇′ are independently hydrogen, alkanyl orsubstituted alkanyl.
 20. The compound of claim 1, wherein R₃′, R₅′ andR₇′ are hydrogen or methyl.
 21. The compound of claim 1, wherein R₉ ishydrogen, alkoxy, substituted alkoxy, halo, oxo, thio, hydroxy or isabsent.
 22. The compound of claim 1, wherein R₉ is alkoxy, oxo orhydroxy.
 23. The compound of claim 1, wherein R₁₀ is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or is absent.24. The compound of claim 1, wherein R₁₀ is aryl, substituted aryl,heteroaryl or substituted heteroaryl.
 25. The compound of claim 1,wherein R₁₁ and R₁₂ are independently hydrogen, alkyl, alkoxy, amino,alkylamino, dialkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, carboxy, cyano, halo, oxo,thio, heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl or hydroxy.
 26. The compound of claim 1,wherein R₁₁ and R₁₂ are independently hydrogen, aryl, substituted aryl,arylalkyl, substituted arylalkyl, oxo, heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl orhydroxy.
 27. The compound of claim 1, wherein R₁₁ and R₁₂ areindependently hydrogen, aryl or substituted aryl.
 28. The compound ofclaim 1, wherein R₁, R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇, R₇′ and R₈ arehydrogen, alkyl or arylalkyl and R₄ and R₅′ are absent.
 29. The compoundof claim 1, wherein R₁ is methyl, R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇, R₇′and R₈ are hydrogen and R₄ and R₅′ are absent.
 30. The compound of claim28 or 29, wherein R₉ is alkoxy, oxo or hydroxy.
 31. The compound ofclaim 28 or 29, wherein R₁₀ is aryl, substituted aryl, heteroaryl orsubstituted heteroaryl.
 32. The compound of claim 28 or 29, wherein A iscarbon, B and C are nitrogen, R₁₁ is hydrogen and R₁₂ is aryl,substituted aryl, heteroaryl or substituted heteroaryl.
 33. The compoundof claim 28 or 29, wherein A is sulfur, B is carbon and C is nitrogen.34. The compound of claim 28 or 29 wherein A is carbon, B is oxygen andC is nitrogen.
 35. The compound of claim 28 or 29, wherein A is carbon,B is nitrogen and C is oxygen.
 36. The compound of claim 1, wherein R₁is methyl, R₂, R₂′, R₃, R₃′, R₅, R₆, R₆′, R₇, R₇′ and R₈ are hydrogen,R₄ and R₅′ are absent, R₉ is alkoxy, oxo or hydroxy, R₁₀ is aryl,substituted aryl, heteroaryl or substituted heteroaryl, A is carbon, Band C are nitrogen, R₁₁ is hydrogen and R₁₂ is aryl, substituted aryl,heteroaryl or substituted heteroaryl.
 37. The compound of claim 36wherein R₉ is hydroxy and R₁₀ is


38. The compound of claim 1, wherein W is oxygen, and R₈, R₉ and R₁₀ areall absent.
 39. The compound of claim 1, wherein R₁₀ and R₂ bonddirectly to one another to form a 5-membered ring, W is nitrogen, R₉ ishydrogen, R₆ and R₂′ are both absent, and a benzene ring is fused to thebond between R₁₀ and R₂.
 40. A method for treating or preventingobesity, diabetes, anxiety, depression, neurodegeneration or aninflammatory disease in a patient comprising administering to a patientin need of such treatment or prevention a therapeutically effectiveamount of a compound according to claim
 1. 41. A pharmaceuticalcomposition comprising the compound of claim
 1. 42. A method fortreating or preventing obesity, diabetes, anxiety, depression,neurodegeneration or an inflammatory disease in a patient, the methodcomprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a composition accordingto claim
 41. 43. A method for selectively modulating the activation,repression, agonism, or antagonism effects of the glucocorticoidreceptor in a patient, comprising administering to said patient atherapeutically effective amount of a composition according to claim 41.44. A method for selectively modulating the activation, repression,agonism, or antagonism effects of the glucocorticoid receptor in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound according to claim
 1. 45. Apharmaceutical composition comprising the compound of claim 1 fortreating or preventing obesity, diabetes, anxiety, depression,neurodegeneration or an inflammatory disease in a patient in need ofsuch treatment.
 46. A compound according to claim 1, wherein thecompound is an antagonist of the glucocorticoid receptor.
 47. A compoundaccording to claim 1, wherein the compound is an agonist of theglucocorticoid receptor.
 48. A method of synthesizing a compoundaccording to claim 1, the method comprising: derivatizing aWieland-Miescher ketone.
 49. A method of synthesizing a compoundaccording to claim 1, the method comprising: preparing an intermediateof formula

and derivatizing the intermediate to produced the compound.